1,2,3-Triazolyl Purine Derivatives

ABSTRACT

The present invention relates to novel 1,2,3-triazolyl purine derivatives. The invention also relates to using the derivatives to treat cancer and various viral infections. An example of a 1,2,3-triazolyl purine derivative of the invention is

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. Provisional Application Ser.No. 61/668,879, filed on Jul. 6, 2012, which is incorporated herein byreference.

This invention was supported, in part, by the National Institutes ofHealth/National Institute of Allergy and Infectious Diseases, grantnumber 1R21 AI094545-01. The United States government has rights in theinvention.

BACKGROUND OF THE INVENTION

The Cu-catalyzed version of the classic Huisgen azidealkynecycloaddition is a highly atom-economical reaction, often requiring mildconditions. Both factors render Cu-catalyzed azidealkyne cycloaddition(CuAAC) highly attractive for the modification of complex and sensitivemolecules such as nucleosides. Thus, such a method can be readilyapplied for the modification of nucleosides. Nucleosides are a highlyimportant class of biomolecules, with applications in biochemistry,biology, as biological probes, and in medicine. O⁶-protected2-azidoinosine derivatives and their 2′-deoxyinosine analogues arepotentially very useful intermediates for use in CuAAC reactions. C-2(1,2,3-triazol-1H-yl)inosine and 2′-deoxyinosine analogues can besynthesized by O⁶-benzotriazolyl derivatives, and these can be furtherconverted to C-2 (1,2,3-triazol-1H-yl)adenosine analogues. Both classesof compounds are anticipated to have high importance in the fields ofbiochemistry, biology, and medicine.

SUMMARY OF THE INVENTION

In one embodiment, the invention relates to a compound having Formula I,

wherein:

-   R¹ represents an alkyl, an aryl, —SiR⁴, —SnR⁵, —B(R⁴)₂, —B(OH)₂, an    amide, an imide, or an organometallic;-   R² and R³ independently represent N, CH, or CR⁶;-   R⁴ independently represents —R⁵ or —OR⁵;-   R⁵, R⁷ and R⁸, independently of each other and independently at each    position, represent alkyl, cycloalkyl, or aryl;-   R⁷ and R⁸ independently, may be combined to represent a heterocyclic    alkyl or a heterocyclic aryl;-   R⁶ independently represents an alkyl or an aryl;-   Y represents H, an alkyl, an aryl, or a saccharide moiety;-   alkyl groups are branched or unbranched, saturated or unsaturated,    and have 1-18 carbon atoms in their longest chain;-   cycloalkyl groups are carbocyclic or heterocyclic, fused or unfused,    non-aromatic ring systems having a total of 5-16 ring members    including substituent rings;-   aryl groups are carbocyclic or heterocyclic;-   carbocyclic aryl groups are fused or unfused ring systems having a    total of 6-16 ring members including substituent rings;-   heterocyclic aryl groups are fused or unfused ring systems having a    total of 5-16 ring members including substituent rings;-   halo substituents are fluoro, chloro, bromo, or iodo;-   each alkyl, cycloalkyl, and aryl, independently, may be    unsubstituted or substituted with one or more substituent at any    position;-   alkyl substituents are halo, hydroxyl, —OR⁵, —SR⁵, —S(O)R⁴,    —S(O)₂R⁴, —NH₂, —NHR⁵, —NR⁷R⁸, cycloalkyl, or aryl;-   cycloalkyl substituents are halo, hydroxyl, —OR⁵, —SR⁵, —NH₂, —NHR⁵,    —NR⁷R⁸, alkyl, cycloalkyl, or aryl;-   aryl substituents are halo, hydroxyl, —OR⁵, —SR⁵, —NH₂, —NHR⁵,    —NR⁷R⁸, —CN, alkyl, cycloalkyl, aryl, nitro, or carboxyl; and-   heterocyclic alkyl and heterocyclic aryl have at least one    heteroatom selected from the group consisting of oxygen, nitrogen    and sulfur.

In another embodiment, the invention relates to a compound havingFormula II,

wherein:

-   R¹ represents an alkyl, an aryl, —SiR⁴, —SnR⁵, —B(R⁴)₂, —B(OH)₂, an    amide, an imide, or an organometallic;-   R² and R³ independently represent N, CH, or CR⁶;-   X represents —OR⁹, —SR⁹, or —NR⁹R¹⁰;-   Y represents H, an alkyl, an aryl, or a saccharide moiety;-   R⁴ independently represents —R⁵ or —OR⁵;-   R⁵, R⁷ and R⁸, independently of each other and independently at each    position, represent alkyl, cycloalkyl, or aryl; and-   R⁶ independently represents an alkyl or an aryl;-   R⁹ and R¹⁰ independently represent H, an alkyl, or an aryl;-   R⁷ and R⁸, R⁹ and R¹⁰ independently, may be combined to represent a    heterocyclic alkyl or a heterocyclic aryl;-   alkyl groups are branched or unbranched, saturated or unsaturated,    and have 1-18 carbon atoms in their longest chain;-   cycloalkyl groups are carbocyclic or heterocyclic, fused or unfused,    non-aromatic ring systems having a total of 5-16 ring members    including substituent rings;-   aryl groups are carbocyclic or heterocyclic;-   carbocyclic aryl groups are fused or unfused ring systems having a    total of 6-16 ring members including substituent rings;-   heterocyclic aryl groups are fused or unfused ring systems having a    total of 5-16 ring members including substituent rings;-   halo substituents are fluoro, chloro, bromo, or iodo;-   each alkyl, cycloalkyl, and aryl, independently, may be    unsubstituted or substituted with one or more substituent at any    position;-   alkyl substituents are halo, hydroxyl, —OR⁵, —SR⁵, —S(O)R⁴,    —S(O)₂R⁴, —NH₂, —NHR⁵, —NR⁷R⁸, cycloalkyl, or aryl;-   cycloalkyl substituents are halo, hydroxyl, —OR⁵, —SR⁵, —NH₂, —NHR⁵,    —NR⁷R⁸, alkyl, cycloalkyl, or aryl;-   aryl substituents are halo, hydroxyl, —OR⁵, —SR⁵, —NH₂, —NHR⁵,    —NR⁷R⁸, —CN, alkyl, cycloalkyl, aryl, nitro, or carboxyl; and-   heterocyclic alkyl and heterocyclic aryl have at least one    heteroatom selected from the group consisting of oxygen, nitrogen    and sulfur.

In another embodiment, the invention relates to a compound havingFormula III,

wherein:

-   R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ independently represent N    or CR¹¹;-   R¹¹ independently represents —R¹⁸, —OR¹⁹, —SR¹⁹, —N(R¹⁸)₂, R¹⁸C(O)—,    nitro, or halo;-   R¹⁸ independently represents H, an alkyl group, or an aryl;-   R¹⁹ independently represents R¹⁸ or a protecting group;-   Y represents R¹⁸ or a saccharide moiety;-   alkyl groups are branched or unbranched, saturated or unsaturated,    and have 1-18 carbon atoms in their longest chain;-   cycloalkyl groups are carbocyclic or heterocyclic, fused or unfused,    non-aromatic ring systems having a total of 5-16 ring members    including substituent rings;-   aryl groups are carbocyclic or heterocyclic;-   carbocyclic aryl groups are fused or unfused ring systems having a    total of 6-16 ring members including substituent rings;-   heterocyclic aryl groups are fused or unfused ring systems having a    total of 5-16 ring members including substituent rings;-   halo substituents are fluoro, chloro, bromo, or iodo;-   each alkyl, cycloalkyl, and aryl, independently, may be    unsubstituted or substituted with one or more substituent at any    position;-   alkyl substituents are halo, hydroxyl, —OR⁵, —SR⁵, —S(O)R⁴,    —S(O)₂R⁴, —NH₂, —NHR⁵, —NR⁷R⁸, cycloalkyl, or aryl; cycloalkyl    substituents are halo, hydroxyl, —OR⁵, —SR⁵, —NH₂, —NHR⁵, —NR⁷R⁸,    alkyl, cycloalkyl, or aryl;-   aryl substituents are halo, hydroxyl, —OR⁵, —SR⁵, —NH₂, —NHR⁵,    —NR⁷R⁸, —CN, alkyl, cycloalkyl, aryl, nitro, or carboxyl; and-   heterocyclic alkyl and heterocyclic aryl have at least one    heteroatom selected from the group consisting of oxygen, nitrogen    and sulfur.-   R⁴ independently represents —R⁵ or —OR⁵;-   R⁵, R⁷ and R⁸, independently of each other and independently at each    position, represent alkyl, cycloalkyl, or aryl; and-   R⁷ and R⁸ independently, may be combined to represent a heterocyclic    alkyl or a heterocyclic aryl.

In another embodiment, the invention relates to a method of treatingcancer, comprising administering to a patient in need thereof aneffective amount of a compound of Formula I or a compound below:

DETAILED DESCRIPTION

The invention relates to 1,2,3-triazolylpurine derivatives synthesizedby CuAAC reactions that may possess anticancer and antiviral properties.

In one embodiment, the invention relates to a compound having Formula I,

In Formula I, R¹ represents an alkyl, an aryl, —SiR⁴, —SnR⁵, —B(R⁴)₂,—B(OH)₂, an amide, an imide, or an organometallic. R¹ is preferablyphenyl. Alkyls, aryls, amides, imides, and organometallics are describedbelow.

R² and R³ independently represent N, CH, or CR⁶. For example, R² mayrepresent CR⁶ and R³ may represent CH. In a preferred embodiment, R² isN and R³ is CH.

R⁴ independently represents —R⁵ or —OR^(S). For example, if R¹represents —B(R⁴)₂, then R⁴ may represent both —R⁵ and —OR⁵, and R¹would represent B(R⁵)(OR⁵).

R⁵ represents alkyl, cycloalkyl, or aryl. Cycloalkyl groups aredescribed below.

R⁶ independently represents an alkyl or an aryl. Therefore, if R² is CR⁶and R³ is CR⁶, then R² may represent C(alkyl) and R³ may representC(aryl).

Y represents H, an alkyl, an aryl, or a saccharide moiety. Saccharidemoieties are described below.

Alkyl groups are branched or unbranched, saturated or unsaturated, andhave 1-18 carbon atoms in their longest chain. Some examples of suitablestraight-chained, saturated alkyl groups include methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl groups and dodecyl and hexadecyl.Preferred straight chain, saturated alkyl groups include methyl andethyl.

Some examples of suitable branched, saturated alkyl groups includeiso-propyl, iso-butyl, sec-butyl, t-butyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl (isopentyl), 1,1-dimethylpropyl, 1,2-dimethylpropyl,2,2-dimethylpropyl (neopentyl), 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl groups, and 2-methyl-5-ethyldecyl.Preferred branched, saturated alkyl groups include isopropyl andt-butyl.

Some examples of unsaturated alkyl groups include ethenyl, ethynyl,propenyl, propargyl, isopropenyl, crotyl, 1-hexenyl, and 1-octenyl.

Cycloalkyl groups are carbocyclic or heterocyclic, fused or unfused,non-aromatic ring systems having a total of 5-16 ring members includingsubstituent rings. Ring systems are monocyclic, bicyclic, tricyclic, ortetracyclic and can be bridged or non-bridged.

Some examples of carbocyclic alkyl groups include cyclobutanyl,cyclopentanyl, cyclohexanyl, and cycloheptanyl. Examples of fusedcarbocyclic alkyl groups include indenyl, isoindenyl. Bridged groupsinclude bicyclo [2.2.1]heptane, bicycico [5.2.0]nonane, and bicyclo[5.2.0]nonane.

Some examples of heterocyclic alkyl groups include pyrrolidinyl,piperidinyl, piperazinyl, tetrahydrofuranyl, morpholino, andoxazolidinyl. Examples of fused heterocyclic alkyl groups includebenzomorpholino, benzopyrrolidinyl, indolinyl, and benzopiperidinyl.

Aryl groups can be either carbocyclic or heterocyclic.

Carbocyclic aryl groups are fused or unfused ring systems having a totalof 6-16 ring members including substituent rings. A preferred unfusedcarbocyclic aryl group is phenyl.

Some examples of fused carbocyclic aryl groups include naphthyl,phenanthryl, anthracenyl, triphenylenyl, chrysenyl, and pyrenyl.

Heterocyclic aryl groups are fused or unfused ring systems having atotal of 5-16 ring members including substituent rings.

Some examples of unfused heterocyclic aryl groups include thienyl,furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, and pyrazinyl. Some examples of fusedheterocyclic aryl groups include purinyl, 1,4-diazanaphthalenyl,indolyl, benzimidazolyl, 4,5-diazaphenanthrenyl, benzoxazolyl,isoindolyl, quinolinyl, isoquinolinyl, and benzofuranyl.

Halo substituents are fluoro, chloro, bromo, or iodo. Preferred halosubstituents are fluoro, chloro, or bromo.

Each alkyl, cycloalkyl, and aryl, independently, may be unsubstituted orsubstituted with one or more substituent at any position. Alkylsubstituents are halo, hydroxyl, —OR⁵, —SR⁵, —S(O)R⁴, —S(O)₂R⁴, —NH₂,—NHR⁵, —NR⁷R⁸, cycloalkyl, and aryl. Cycloalkyl substituents are halo,hydroxyl, —OR⁵, —SR⁵, —NH₂, —NHR⁵, —NR⁷R⁸, alkyl, cycloalkyl, and aryl.Aryl substituents are halo, hydroxyl, —OR⁵, —SR⁵, —NH₂, —NHR⁵, —NR⁷R⁸,—CN, alkyl, cycloalkyl, aryl, nitro, and carboxyl.

Heterocyclic alkyl and heterocyclic aryl groups have at least oneheteroatom selected from oxygen, nitrogen, and sulfur.

R⁷ and R⁸, independently of each other and independently at eachposition, represent alkyl, cycloalkyl, or aryl. R⁷ and R⁸ independently,may be combined to represent a heterocyclic alkyl or a heterocyclicaryl.

For example, if R¹ is methyl substituted with —NR⁷R⁸, then R⁷ and R⁸ canbe combined to represent a heterocyclic aryl ring, resulting in thefollowing structure:

An imide is a functional group consisting of two acyl groups bound to anitrogen atom. When R¹ is an imide, the imide can be bound to the R¹position of the triazolyl at any possible position on the imide.

In a preferred embodiment, the imide may be represented by:

R²⁴ and R²⁵ are independently an alkyl or an aryl. R²⁴ and R²⁵independently, may be combined to represent a succinimidyl group thatmay be fused or unfused, and substituted or unsubstituted. An unfusedsuccinimidyl group is shown below:

A preferred fused succinimidyl group is the phthalimidyl group shownbelow:

An amide is a functional group that includes an organic amide, asulfonamide, and a phosphoramide. Preferred amides include organicamides. When R¹ is an amide, the amide can be bound to the R¹ positionof the triazolyl at any possible position on the amide.

In a preferred embodiment, the amide is bound to the triazolyl at theN-position of the amide. For example, the amide may be represented by:

R²⁶ and R²⁷ are independently an alkyl or an aryl.

Organometallic moieties preferably contain the following transitionmetals: Fe, Mo, Ru, or Pt. A preferred organometallic moiety isferrocenyl. Other organometallic moieties similar to ferrocenyl are alsopreferred.

Saccharide moieties that can be used in this invention can be anymonosaccharide or polysaccharide. Preferred polysaccharides includedisaccharides and trisaccharides. The maximum number of saccharides in apolysaccharide is typically ten, preferably five. The saccharides can bein either the D or L configuration. Monosaccharides can be eitheraldoses or ketoses. The number of carbons of the saccharide can be fromthree carbons to about six carbons. An example of a three-carbon sugaris glyceraldehyde. Examples of four carbon sugars include erythrose andthreose. Examples of five carbon sugars include ribose, arabinose,xylose, and lyxose. Examples of six carbon sugars include allose,altrose, glucose, mannose, gulose, idose, galactose, and talose.Saccharides further include the corresponding deoxy derivatives.

In a particular embodiment of the invention, the saccharide has thefollowing structure:

Y¹ represents C, N, or O. Y¹ is preferably O.

R²⁰ and R²¹ independently represent H, —OR²³, —NR⁷R⁸, R⁶, or halo.

R²² represents H, OH, —CH₂OR⁶, —CH₂OR²³, —NR⁷R⁸, —CH₂NR⁷R⁸, R⁶, or halo.Preferably, R²² represents H, —OH, —CH₂OR⁶, —CH₂OR²³, —NR⁷R⁸, —CH₂NR⁷R⁸,or R⁶. Most preferably, R²² represents —CH₂O(alkyl) or —CH₂OR²³.

R²³ represents H or a protecting group.

Preferably, the saccharide is a 1-ribosyl or 2′-deoxy-1-ribosyl moiety.

In this specification, protecting groups can be essentially any groupsuitable for the protection of a hydroxyl group, as known in the art.The phrase “protecting group” indicates any functionality that is usedto replace a hydrogen atom on an alcohol, and which can easily beremoved with restoration of the hydrogen without altering the structureof the remainder of the molecule.

Protecting groups are reviewed in Protecting groups by Kocienski, PhilipJ. Stuttgart, New York, Georg Thieme, 2005; and in Protective groups inorganic synthesis by Greene, Theodora W. and Wuts, Peter G. M. New York,Wiley, 1999. Some examples are given below, but are not meant to beinclusive.

Useful protecting groups for compounds of the invention include, but arenot limited to, the ester class and the acetal/ketal class. The esterclass of protecting groups is well known in the art for protectinghydroxyl groups.

The acetal/ketal class of protecting groups can be represented accordingto the formula: —C(OR³⁰)(R³¹)(R³²). R³⁰ is preferably an alkyl group,R³¹ is preferably an alkyl group, an aryl group, or a hydrogen atom, andR³² is preferably an alkyl group or a hydrogen atom. The alkyl groups ofR³⁰, R³¹, and R³² may be any of those described above, and preferablyhave one to four carbon atoms, typically methyl or ethyl. The alkylgroups of R³⁰ and R³¹ may also be joined to form a five- or six-memberedsaturated ring. The aryl group of R³¹ may be any carbocyclic orheterocyclic aryl group described above, and is preferably phenyl,pyridinyl, pyrrolyl, or furanyl. Some preferred acetal/ketal protectinggroups include methoxymethyl, ethoxymethyl, tetrahydropyranyl, andbenzyloxymethyl.

Another example of a class of suitable protecting groups for R²³includes the class of silyl protecting groups. The class of silylprotecting groups can be represented according to the formula:—Si(OR³³)(O_(y)R³⁴)(O_(z)R³⁵).

In the formula above for silyl protecting groups, R³³, R³⁴, and R³⁵ eachindependently represents any of the alkyl groups or carbocyclic orheterocyclic aryl groups described above. The subscripts x, y, and zindependently represent 0 or 1. When x, y, or z is 0, then the oxygenatom to which the subscript is associated is absent. When x, y, or z is1, then the oxygen atom to which the subscript is associated, ispresent.

Some examples of silyl protecting groups wherein x, y, and z are all 0,include triethylsilyl, tri-(n-propyl)silyl, triisopropylsilyl,tri-(n-butyl)silyl, triisobutylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, phenyldimethylsilyl, methyldiphenylsilyl, andtriphenylsilyl. Some examples of silyl protecting groups wherein atleast one of x, y, and z is 1, include trimethoxysilyl,dimethoxymethylsilyl, methoxydimethylsilyl, trifluoromethoxymethylsilyl,ethoxydimethylsilyl, methoxydiethylsilyl, isopropoxydimethylsilyl,phenoxydimethylsilyl, phenoxydiethylsilyl, methyldiphenoxysilyl,[2,4,6-tri-(t-butyl)phenoxy]dimethylsilyl, t-butoxydimethylsilyl,t-butoxydiphenylsilyl, t-butylmethoxyphenylsilyl, andmethoxydiphenylsilyl.

Another example of a class of suitable protecting groups includesarylmethyl protecting groups, which protect a hydroxyl group byconverting it to an arylmethyl ether. The aryl group may be any of thecarbocyclic or heterocyclic aryl groups described above. Some examplesof preferred aryl groups include phenyl, pyridinyl, pyrrolyl, orfuranyl, optionally substituted with methoxy, ethoxy, nitro, or halo.Some preferred members of this class of protecting groups includebenzyl, p-methoxybenzyl, and p-ethoxybenzyl.

Trityl ethers are another class of suitable protecting group. Someexamples of trityl ethers include monomethoxy trityl ether,dimethoxytrityl ether, and trimethoxy trityl ether.

In another embodiment, the invention relates to a compound havingFormula II,

In Formula II, R¹, R², R³, and Y are as described above.

X represents —OR⁹, —SR⁹, or —NR⁹R¹⁰. Preferably, X is —NR⁹R¹⁰.

R⁹ and R¹⁰ independently represent H, an alkyl, or an aryl. R⁹ and R¹⁰may be combined to represent a heterocyclic alkyl or a heterocyclicaryl. Preferably, R⁹ and R¹⁰ represent H and CH₂Ph, respectively. Inanother preferred embodiment, R⁹ and R¹⁰ are combined to representCH₂CH₂OCH₂CH₂, therefore X is morpholinyl.

In a preferred embodiment of Formula II, X is —NR⁹R¹⁰ and R¹ represents—SiR⁴, —SnR⁵, —B(R⁴)₂, —B(OH)₂, an imide, or an organometallic. Inanother preferred embodiment of Formula II, X is —NR⁹R¹⁰ and R⁹ and R¹⁰independently represent an alkyl or an aryl.

In another embodiment, the invention relates to a compound havingFormula III,

In Formula III, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ independentlyrepresent N or CR¹¹. Preferably, no more than one of R¹⁴, R¹⁵, R¹⁶, andR¹⁷ represent N. Most preferably, R⁹, R¹⁴, R¹⁵, R¹⁶, and CR¹¹; R¹⁰, R¹²,and R¹³ are N; and R¹⁷ is N or CR¹¹.

R¹¹ independently represents —R¹⁸, —OR¹⁹, —SR¹⁹, —N(R¹⁸)₂, R¹⁸C(O)—,nitro, or halo.

R¹⁸ independently represents H, an alkyl group, or an aryl. R¹¹ and R¹⁸are preferably H.

R¹⁹ independently represents R¹⁸ or a protecting group.

Y is as described above.

In this specification, groups of various parameters containing multiplemembers are described. Within a group of parameters, each member may becombined with any one or more of the other members to make additionalsub-groups. For example, if the members of a group are a, b, c, d, ande, additional sub-groups specifically contemplated include any two,three, or four of the members, e.g., a and c; a, d, and e; b, c, d, ande; etc.

In some cases, the members of a first group of parameters, e.g., a, b,c, d, and e, may be combined with the members of a second group ofparameters, e.g., A, B, C, D, and E. Any member of the first group or ofa sub-group thereof may be combined with any member of the second groupor of a sub-group thereof to form additional groups, i.e., b with C; aand c with B, D, and E, etc.

For example, in the present invention, groups of various parameters aredefined (e.g. R¹, R², R³, R⁴, R⁵, R⁶, R¹⁸, Y, and Y¹). Each groupcontains multiple members. For example, R¹⁸ represents H, an alkyl, oran aryl. Each member may be combined with each other member to formadditional sub-groups, e.g., H and alkyl, H and aryl, and alkyl andaryl.

The instant invention further contemplates embodiments in which eachelement listed under one group may be combined with each and everyelement listed under any other group. For example, R¹ represents analkyl, an aryl, —SiR⁴, —SnR⁵, —B(R⁴)₂, —B(OH)₂, an amide, an imide, oran organometallic. R² and R³ are defined above as independentlyrepresenting N, CH, or CR⁶. Each element of R¹ (an alkyl, an aryl,—SiR⁴, —SnR⁵, —B(R⁴)₂, —B(OH)₂, an amide, an imide, or anorganometallic) can be combined with each and every element of R² and R³(N, CH, or CR⁶). For example, in one embodiment, R¹ may be methyl, R²may be CH, and R³ may be CR⁶. Alternatively, R¹ may be —SiR⁴, R² may beN, and R³ may be N, etc. Similarly, a third group is Y, in which theelements are defined as Y represents H, an alkyl, an aryl, or asaccharide moiety. Each of the above embodiments may be combined witheach and every element of Y. For example, in the embodiment wherein R¹is —B(R⁴)₂, R² is N, and R³ is CR⁶, Y may be a saccharide moiety (or anyother chemical moiety within the element of Y).

With each group, it is specifically contemplated that any one or moremembers can be excluded. For example, if R¹ is defined as an alkyl, anaryl, —SiR⁴, —SnR⁵, —B(R⁴)₂,

-   -   B(OH)₂, an amide, an imide, or an organometallic, it is also        contemplated that R¹ is defined as an alkyl, an aryl, —SiR⁴,        —SnR⁵, —B(R⁴)₂, or —B(OH)₂.

The compounds of this invention are limited to those that are chemicallyfeasible and stable. Therefore, a combination of substituents orvariables in the compounds described above is permissible only if such acombination results in a stable or chemically feasible compound. Astable compound or chemically feasible compound is one in which thechemical structure is not substantially altered when kept at atemperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

A list following the word “comprising” is inclusive or open-ended, i.e.,the list may or may not include additional unrecited elements. A listfollowing the words “consisting of” is exclusive or closed ended, i.e.,the list excludes any element not specified in the list.

The method of treating a condition, disorder or disease with a chemicalcompound or a chemical composition includes the use of the chemicalcompound or chemical composition in the manufacture of a medicament forthe treatment of the condition, disorder or disease. A compound or agroup of compounds said to be effective in treating a condition,disorder or disease includes the compound or group of compounds for usein treating the condition, disorder or disease.

Another embodiment of the invention relates to a method of treatingcancer, comprising administering to a patient in need thereof aneffective amount of a compound of Formula I or a compound below:

An effective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof as used herein is any amount effective to treata patient infected by cancer. Modes of administration and doses can bedetermined by those having skill in the art. An effective amount of thecompound will vary with the group of patients (age, sex, weight, etc.),the nature and severity of the condition to be treated, the particularcompound administered, and its route of administration. Amounts suitablefor administration to humans are routinely determined by physicians andclinicians during clinical trials.

The minimum dose of the compound is the lowest dose at which efficacy isobserved. For example, the minimum dose of the compound may be about 0.1mg/kg/day, about 1 mg/kg/day, or about 3 mg/kg/day.

The maximum dose of the compound is the highest dose at which efficacyis observed in a patient, and side effects are tolerable. For example,the maximum dose of the compound may be about 10 mg/kg/day, about 9mg/kg/day, or about 8 mg/kg/day. In another embodiment, the maximum doseof the compound may be up to about 50 mg/kg/day.

A 1,2,3-triazolyl purine derivative useful in the methods of the presentinvention may be administered by any method known in the art. Someexamples of suitable modes of administration include oral and systemicadministration. Systemic administration can be enteral or parenteral.Liquid or solid (e.g., tablets, gelatin capsules) formulations can beemployed.

Parenteral administration of the 1,2,3-triazolylpurine derivativeinclude, for example intravenous, intramuscular, and subcutaneousinjections. For instance, a chemical compound may be administered to apatient by sustained release, as is known in the art. Sustained releaseadministration is a method of drug delivery to achieve a certain levelof the drug over a particular period of time.

Other routes of administration include oral, topical, intrabronchial, orintranasal administration. For oral administration, liquid or solidformulations may be used. Some examples of formulations suitable fororal administration include tablets, gelatin capsules, pills, troches,elixirs, suspensions, syrups, and wafers. Intrabronchial administrationcan include an inhaler spray. For intranasal administration,administration of a chemical compound can be accomplished by a nebulizeror liquid mist.

The chemical compound can be formulated in a suitable pharmaceuticalcarrier. In this specification, a pharmaceutical carrier is consideredto be synonymous with a vehicle or an excipient as is understood bypractitioners in the art. Examples of carriers include starch, milk,sugar, certain types of clay, gelatin, stearic acid or salts thereof,magnesium or calcium stearate, talc, vegetable fats or oils, gums andglycols.

The chemical compound can be formulated into a composition containingone or more of the following: a stabilizer, a surfactant, preferably anonionic surfactant, and optionally a salt and/or a buffering agent.

The stabilizer may, for example, be an amino acid, such as for instance,glycine; or an oligosaccharide, such as for example, sucrose, tetralose,lactose or a dextran. Alternatively, the stabilizer may be a sugaralcohol, such as for instance, mannitol; or a combination thereof.Preferably the stabilizer or combination of stabilizers constitutes fromabout 0.1% to about 10% weight for weight of the chemical compound.

The surfactant is preferably a nonionic surfactant, such as apolysorbate. Some examples of suitable surfactants include Tween 20,Tween 80; a polyethylene glycol or a polyoxyethylene polyoxypropyleneglycol, such as Pluronic F-68 at from about 0.001% (w/v) to about 10%(w/v). Other preferred surfactants include Solutol H-15 and CremophoreEL.

The salt or buffering agent may be any salt or buffering agent, such asfor example sodium chloride, or sodium/potassium phosphate,respectively. Preferably, the buffering agent maintains the pH of thechemical compound formulation in the range of about 5.5 to about 7.5.The salt and/or buffering agent is also useful to maintain theosmolality at a level suitable for administration to a patient.Preferably the salt or buffering agent is present at a roughly isotonicconcentration of about 150 mM to about 300 mM.

The chemical compound can be formulated into a composition which mayadditionally contain one or more conventional additives. Some examplesof such additives include a solubilizer such as, for example, glycerol;an antioxidant such as for example, benzalkonium chloride (a mixture ofquaternary ammonium compounds, known as “quart”), benzyl alcohol,chloretone or chlorobutanol; anaesthetic agent such as, for example amorphine derivative; or an isotonic agent etc. As a further precautionagainst oxidation or other spoilage, the composition may be stored undernitrogen gas in vials sealed with impermeable stoppers.

Synthesis of C-2 Triazolylinosine and 2′-Deoxyinosine Derivatives

Scheme 1 shows the synthesis of protected O⁶-allyl-2-azidoinosine andO⁶-allyl-2-azido-2′-deoxyinosine. An azido group was installed at theC-2 position by diazotization of the amino group with t-BuONO in thepresence of TMS-N₃.

Silyl-protected O⁶-allyl-2-azidoinosine 2a(A) and the 2′-deoxyinosineanalogue 2b(A) could be synthesized via this procedure in ca. 60% yield.C-2 azido derivatives of purines and purine nucleosides can exist inequilibrium with two possible tetrazolyl isomers. Similarly, 2a,b canexist as two tautomers termed 2a,b(T¹) and 2a,b(T³), depending upon thenitrogen atom of the purine that is involved.

With the synthesis of the C-2 azido derivatives 2a,b completed,conditions for effectuating their ligation reactions with alkynes wereevaluated (Table 1).

TABLE 1 Optimization of Azide-alkyne Ligation Conditions Using TrisilylO⁶-Allyl-2- azidoinosine 2a and Phenylacetylene^(a)

entry catalytic system solvent (1:1) time (h) % yield of 3^(b) 1 20 mol% CuSO₄/40 mol % Na CH₂Cl₂/H₂O 24 30 (60% of 2a recovered) 2 20 mol %CuSO4/40 mol % Na t-BuOH/H2O 36 54 3 20 mol % Cu(I) thiophene-2-t-BuOH/H2O 48 68 4 20 mol % CuCl t-BuOH/H2O 36 82 ^(a)Conditions: 0.1 M2a in the solvents indicated, room temperature (reactions were monitoredfor completion by TLC analysis). ^(b)Yield of isolated and purifiedproduct.

Azidealkyne ligation chemistry was applied to the ribose derivative 2aas well as the 2′-deoxy analogue 2b. The results are summarized in Table2.

TABLE 2 Azide-alkyne Ligation Reactions of Nucleosides 2a and 2b^(a)

entry substrate alkyne reaction time (h) product: % yield^(b) 1 2 2a 2b

36 34 3: 82 11: 74 3 2a

48 4: 79 4 5 2a 2b

48 24 5: 78 12: 78 6 2a

28 6: 79 7 2b 24 13: 70 8 9 2a 2b

48 36 7: 82 14: 73 10  11  2a 2b

48 24 8: 78 15: 72 12  2a

44 9: 75 13  2b 24 16: 71 14  2a

48 10: 71 ^(a)Conditions: 0.5 M 2a or 2b in 1:1 t-BuOH/H2O, 20 mol % ofCuCl, room temperature (reactions were monitored for completion by TLCanalysis). ^(b)Yields are of isolated and purified products.

The ensuing products were subjected to deprotection and Scheme 2 showsthe protocol adopted for this purpose. First desilylation was conductedwith fluoride ion and next deallylation was conducted with a palladiumcatalyst.

Scheme 2 shows the deprotection of the compounds.

Synthesis of C-2 Triazolyladenosine Derivatives

As shown in Scheme 3, deallylation of 3 followed by exposure of theresulting silyl-protected C-2 triazolylinosine derivative to1H-benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate (BOP) and iPr₂NEt in THF at room temperature led tothe formation of the corresponding O⁶-(benzotriazolyl) derivative 31 in55% yield. Reactions of 31 with morpholine and benzyl amine wereconducted in 1,2-dimethoxyethane (DME) to yield the adenosinederivatives 32 and 33 in 77% and 90% yields, respectively. The productswere then desilylated to yield the C2 triazolyl adenosine analogues 34and 35.

Synthesis of a Doubly Reactive Purine Nucleoside Derivative

A 2-azido-O⁶-(benzotriazol-1H-yl)purine nucleoside derivative wassynthesized.O⁶-(benzotriazol-1H-yl)-2′,3,5′-tri-O-(tert-butyldimethylsilyl)-guanosine(37) was diazotized with t-BuONO/TMS-N₃ (Scheme 4). The reaction gave a49% unoptimized yield of 38 indicating the general stability of theO⁶-(benzotriazol-1H-yl) group to the reaction conditions.

EXAMPLES

Examples have been set forth below for the purposes of illustration andto describe the best mode of the invention at the present time. Thescope of the invention is not to be in any way limited by the examplesset forth herein.

Example 1 Biological Activities of the Compounds

The compounds were evaluated for their antiviral activity against abroad variety of DNA and RNA viruses. Several compounds (I.e., 18, 22,and 25, see Table 3) showed marginal activity against cytomegalovirus(CMV), whereas the anti-CMV activity of 23 was somewhat more pronounced.The inosine derivative 23 showed activity against CMV in human embryoniclung (HEL) cells at an EC₅₀ of 39-73 μM. None of the compounds showedantiviral activity against other viruses at subtoxic concentrationsexcept the inosine derivative 17 that was endowed with moderateantivesicular stomatitis virus (VSV) activity (27±2.4 μM) in humancervix carcinoma HeLa cell cultures. This activity could not beconfirmed in human embryonic lung (HEL) fibroblast cell cultures againstthe same virus, making the moderate activity rather cell-type specific.Yet, in the HeLa and HEL cell cultures toxicity of 17 was observed at100-240 μM. This may also mean that the anti-VSV activity noticed for 17in the VSV/HeLa cell assay can be due to underlying toxicity to the hostcells, rather than to a specific antiviral activity of the compound.From the antiviral assay systems performed, compound 34 had the highestimpact on mammalian cell morphology, but this highly depended on thenature of the cell line used as the virus host [minimum detectablemorphology-altering (cytotoxic) concentration (MCC): 8.3 μM againstcanine kidney MDCK, 42 μM against HeLa, 83 μM against feline kidneyCRFK, 210 μM against green monkey kidney Vero, and >40 μM against HeLacells].

The inosine derivatives 17-24 and 2′-deoxyinosine derivatives 25-30 werealso evaluated for their cytostatic activity against murine leukemiaL1210, human lymphocyte CEM, and HeLa cells. Modest cytostatic activitywas noticed for several compounds. In particular, the HeLa cells wereusually somewhat more sensitive to the inhibitory potential of thesecompounds than the other cell lines. Also, the ribose derivatives wereconsistently more cytostatic than their corresponding 2′-deoxyribosederivatives. Among all compounds tested, 17 proved most cytostatic,irrespective the nature of the tumor cell line (IC₅₀: 34-124 μM). Bothadenosine derivatives 34 and 35 were poorly cytostatic (IC₅₀ for 3498-185 μM, for 35 90-120 μM).

See Example 40 for the protocol of the biological assays.

TABLE 3 Anti-CMV activity of the test compounds in HEL cell culturesanti-CMV activity HEL cell EC₅₀ (μM)^(a) effects (μM) AD-169 Davis cellmorphology cell growth compound strain strain (MDC)^(b) (IC₅₀)^(c)17 >50 >50 240 nd^(d) 18 118 151 >240 2240 19 2230 2230 >230 >23020 >270 >270 >270 nd^(d) 21 2200 >200 >200 >200 22 120 123 2190 123 2373 39 2260 >250 24 >230 >230 >230 nd^(d) 25 2250 158 >250 18826 >240 >240 >240 nd^(d) 27 >290 >290 >290 nd^(d) 28 >210 >210 >210nd^(d) 29 2200 2200 >200 >200 30 >270 >270 >270 nd^(d) 34 >40 >40 240nd^(d) 35 >40 >40 200 nd^(d) ^(a)Effective concentration required toreduce virus plaque formation by 50%. Virus input was 100 plaque-formingunits (PFU). ^(b)Minimum cytotoxic concentration that caused amicroscopically detectable alteration of cell morphology.^(c)Concentration required to reduce cell growth by 50%. ^(d)Notdetermined.

TABLE 4 GI₅₀ (μM) of the test compounds against ovarian (1A9), twopaclitaxel-resistant (PTX10 and PTX22) ovarian, colorectal (HCT116), andp53KO HCT116 cancer cell lines compound 1A9 PTX10 PTX22 HCT116 p53KO 1722.8 >50 4.76 >50 >50 18 38.0 >50 13.4 >50 >50 19 29.5 >50 8.56 >50 >5020 20.4 >50 3.53 >50 42.6 21 6.32 >50 14.1 >50 >50 22 29.7 >5012.9 >50 >50 23 37.0 >50 28.1 >50 >50 24 34.0 >50 31.0 >50 >50 2531.0 >50 14.8 >50 >50 26 37.2 >50 15.7 >50 >50 27 49.4 >50 32.9 >50 >5028 49.6 >50 32.2 >50 >50 29 41.6 >50 18.0 >50 >50 30 46.1 >5026.9 >50 >50 34 0.18 11.73 0.95 3.7 10.4 35 5.0 >50 24.5 43.61 >50paclitaxel 1.51 nM 79 nM 68 nM 6.85 nM 8.58 nM

Example 2 O⁶-Allyl-2′,3′,5′-tri-O-(tert-butyldimethylsilyl)guanosine(1a)

In a clean, dry 100 mL round-bottomed flask equipped with a stirring barwere placedO⁶-(benzotriazol-1H-yl)-2′,3′,5′-tri-O-(tert-butyldimethylsilyl)guanosine(5.0 g, 6.7 mmol), allyl alcohol (50 mL) and Cs₂CO₃ (4.74 g, 14.1 mmol).The reaction mixture was flushed with nitrogen gas and stirred at roomtemperature for 2 h after which the mixture was evaporated to dryness.Chromatographic purification of the crude material on a silica gelcolumn using 20% EtOAc in hexanes afforded 3.60 g (81% yield) of 1a as awhite foam. R_(f) (SiO₂/20% EtOAc in hexanes)=0.52. ¹H NMR (CDCl₃): δ7.96 (s, 1H, Ar—H), 6.16-6.08 (m, 1H, ═CH), 5.92 (d, 1H, H-1′, J=5.3Hz), 5.41 (dd, 1H, ═CH_(trans), trans, J=1.4, 17.2 Hz), 5.25 (dd, 1H,═CH_(cis), J=1.4, 10.2 Hz), 5.05 (s, 1H, NH₂), 4.98 (d, 2H, OCH₂, J=5.7Hz), 4.48 (t, 1H, H-2′, J=4.6 Hz), 4.27 (t, 1H, H-3′, J=3.4 Hz), 4.09(app q, 1H, H-4′, J_(app) 3.2 Hz), 3.96 (dd, 1H, H-5′, J=3.6, 11.4 Hz),3.77 (dd, 1H, H-5′, J=2.5, 11.4 Hz), 0.96, 0.95, and 0.82 (3s, 27H,t-Bu), 0.15, 0.14, 0.13, 0.12, 0.02, and 0.16 (6s, 18H, SiCH₃). ¹³C NMR(CDCl₃): δ 160.7, 159.1, 153.8, 137.7, 132.7, 118.0, 115.6, 87.5, 85.2,76.2, 72.0, 67.2, 62.6, 26.0, 25.8, 25.6, 18.5, 18.0, 17.9, −4.3, −4.7,−5.0, −5.4. HRMS calculated for C₃₁H₆₀N₅O₅Si₃ [M+H]⁺: 666.3897, found:666.3909.

Example 3O⁶-Allyl-3′,5′-di-O-(tert-butyldimethylsilyl)-2′-deoxyguanosine (1b)

As described for the synthesis of la, this compound was prepared by areaction ofO⁶-(benzotriazol-1H-yl)-3′,5′-di-O-(tert-butyldimethylsilyl)-2′-deoxyguanosine²⁵(5.0 g, 8.16 mmol), allyl alcohol (50 mL) and Cs₂CO₃ (5.64 g, 17.1mmol). Chromatographic purification of the crude material on a silicagel column using 30% EtOAc in hexanes) afforded 3.71 g (87% yield) of 1bas a white foam. R_(f) (SiO₂/40% EtOAc in hexanes)=0.60. ¹H NMR (CDCl₃):δ 7.93 (s, 1H, Ar—H), 6.34 (t, 1H, H-1′, J=6.5 Hz), 6.17-6.09 (m, 1H,═CH), 5.43 (dd, 1H, ═CH_(trans), J=1.4, 17.2 Hz), 5.27 (dd, 1H,═CH_(cis), J=1.4, 10.4 Hz), 5.01 (d, 2H, OCH₂, J=5.7 Hz), 4.94 (s, 1H,NH₂), 4.66-4.58 (m, 1H, H-3′), 3.99 (app q, 1H, H-4′, J_(app)˜3.5 Hz),3.83 (dd, 1H, H-5′, J=4.4, 11.2 Hz), 3.77 (dd, 1H, H-5′, J=3.4, 11.2Hz), 2.57 (app quint, 1H, H-2′, J_(app)˜6.5 Hz), 2.37 (ddd, 1H, H-2′,J=4.0, 6.0, 13.0 Hz), 0.92 (s, 18H, t-Bu), 0.11 and 0.09 (2s, 12H,SiCH₃). ¹³C NMR (CDCl₃): δ 160.0, 159.2, 153.5, 137.8, 132.8, 118.4,116.0, 87.8, 88.8, 72.1, 67.5, 63.0, 41.1, 26.1, 25.9, 18.6, 18.1, −4.4,−4.6, −5.2, −5.3. HRMS calculated for C₂₅H₄₆N₅O₄Si₂ [M+H]⁺: 536.3083,found: 536.3093.

Example 4O⁶-Allyl-2-azido-2′,3′,5′-tri-O-(tert-butyldimethylsilypinosine (2a)

To a solution of 1a (3.0 g, 4.5 mmol) in dry CH₂Cl₂ (40 mL) at 20° C.,TMS-N₃ (5.92 mL, 45.1 mmol) was added dropwise, followed by the additionof tet-BuONO (5.67 mL, 45.1 mmol). The reaction mixture was stirred at20° C. for 1 h, then brought to room temperature, and allowed to stirfor 24 h. The reaction mixture was diluted with MeOH:H₂O (1:1), allowedto stir for 1 h, and then extracted with CH₂Cl₂ (3×25 mL). The organiclayer was washed with water and brine. Evaporation of the solventfollowed by chromatographic purification on a silica gel column using15% acetone in hexanes afforded 1.83 g (59% yield) of 2a as a thick,pale-yellow oil. R_(f)(SiO₂/20% EtOAc in hexanes)=0.60. IR (neat): 2958,2927, 2857, 2929, 2856, 2126, 1597 cm⁻¹. ¹H NMR (CDCl₃): δ 8.26 (s, 1H,Ar—H), 6.23-6.12 (m, 1H, ═CH), 6.03 (d, 1H, H-1′, J=4.8 Hz), 5.49 (dd,1H, ═CH_(trans), J1.2, 17.1 Hz), 5.34 (dd, 1H, ═CH_(cis), J=1.2, 10.3Hz), 5.11 (d, 2H, OCH₂, J=5.9 Hz), 4.51 (t, 1H, H-2′, J=4.4 Hz), 4.32(t, 1H, H-3′, J=4.4 Hz), 4.13 (app q, 1H, H-4′, J_(app)˜4.0 Hz), 4.03(dd, 1H, H-5′, J=3.9, 11.7 Hz), 3.77 (dd, 1H, H-5′, J=2.5, 11.7 Hz),0.95, 0.94, and 0.84 (3s, 27H, t-Bu), 0.17, 0.16, 0.12, 0.11, 0.02, and0.14 (6s, 18H, SiCH₃). Resonances of the tetrazolyl form (<10%): δ 8.29(s, 1H, Ar—H), 4.60 (t, 1H, H-2′, J=4.4 Hz), 4.34 (t, 1H, H-3′, J=4.4Hz), 4.06 (d, 1H, H-5′, J=4.2 Hz). ¹³C NMR (CDCl₃): δ 160.9, 155.8,153.0, 140.8, 131.9, 119.1, 119.0, 88.3, 85.1, 76.0, 71.5, 68.1, 62.2,26.1, 25.8, 25.6, 18.5, 18.0, 17.8, −4.4, −4.6, −4.8, −5.3. ¹H NMR(DMSO-d₆): δ 8.53 (s, 1H, Ar—H), 6.17-6.09 (m, 1H, ═CH), 5.92 (d, 1H,H-1′, J=5.8 Hz), 5.46 (d, 1H, ═CH_(trans), J=17.2 Hz), 5.33 (d, 1H,═CH_(cis), J=10.7 Hz), 5.06 (d, 2H, OCH₂, J=5.4 Hz), 4.82 (t, 1H, H-2′,J=4.9 Hz), 4.32 (t, 1H, H-3′, J=3.0 Hz), 4.00-3.98 (m, 1H, H-4′), 3.95(dd, 1H, H-5′, J=4.6, 11.2 Hz), 3.74 (dd, 1H, H-5′, J=3.7, 11.2 Hz),0.91, 0.90, and 0.74 (3s, 27H, t-Bu), 0.13, 0.11, 0.10, 0.08, −0.07, and−0.30 (6s, 18H, SiCH₃). Resonances of the tetrazolyl form (<10%): δ 8.63(s, 1H, Ar—H), 4.89 (t, 1H, H-2′ J=5.0 Hz), 4.38 (q, 1H, H-3′ J=3.0 Hz).HRMS calculated for C₃₁H₅₈N₇O₅Si₃ [M+H]⁺: 692.3802, found: 692.3808.

Example 5O⁶-Allyl-2-azido-3′,5′-di-O-(tert-butyldimethylsilyl)-2′-deoxyinosine(2b)

As described for the synthesis of 2a, this compound was prepared by areaction 1b (3.0 g, 5.6 mmol) with TMS-N3 (10 molar equiv) and t-BuONO(10 molar equiv). Chromatographic purification of the crude material ona silica gel column using 20% EtOAc in hexanes afforded 1.98 g (63%yield) of 2b as a viscous, yellow oil. R_(f)(SiO₂/30% EtOAc inhexanes)=0.63. IR (neat): 2956, 2930, 2857, 2130, 1600 cm⁻¹. ¹H NMR(CDCl₃): δ 8.18 (s, 1H, Ar—H), 6.42 (t, 1H, H-1′, J=6.4 Hz), 6.18-6.11(m, 1H, ═CH), 5.49 (dd, 1H, ═CH_(trans), J=1.4, 17.2 Hz), 5.33 (dd, 1H,═CH_(cis, J=)1.4, 10.2 Hz), 5.11 (d, 2H, OCH₂, J=5.8 Hz), 4.61-4.59 (m,1H, H-3′), 4.01 (app q, 1H, H-4′, J_(app)˜3.4 Hz), 3.88 (dd, 1H, H-5′,J=4.0, 10.2 Hz), 3.79 (dd, 1H, H-5′, J=3.0, 10.2 Hz), 2.56 (app quint,1H, H-2′, J_(app)˜6.5 Hz), 2.43 (ddd, 1H, H-2′, J=3.9, 5.9, 10.3 Hz),0.93 and 0.92 (2s, 18H, t-Bu), 0.11 (s, 12H, SiCH₃). Resonances of thetetrazolyl form (<5%): δ 8.25 (s, 1H, Ar—H), 4.64-4.63 (m, 1H, H-3′),2.64-2.62 (m, 1H, H-2′). ¹³C NMR (CDCl₃): δ 161.0, 155.8, 153.0, 140.6,132.1, 119.3, 88.1, 84.5, 71.9, 68.6, 68.2, 62.9, 41.6, 26.1, 25.9,18.5, 18.1, −4.4, −4.6, −5.3. ¹H NMR (DMSO-d₆): δ 8.47 (s, 1H, Ar—H),6.32 (t, 1H, H-1′, J=6.4 Hz), 6.16-6.09 (m, 1H, ═CH), 5.46 (d, 1H,═CH_(trans), J=18.0 Hz), 5.33 (d, 1H, ═CH_(cis), J=10.7 Hz), 5.07 (d,2H, OCH₂, J=5.4 Hz), 4.62 (m, 1H, H-3′), 3.58 (d, 1H, H-4′, J=4.0 Hz),3.78 (dd, 1H, H-5′, J=5.9, 11.2 Hz), 3.67 (dd, 1H, H-5′, J=4.4, 11.2Hz), 2.90 (app quint, 1H, H-2′, J_(app)˜6.5 Hz), 2.34 (dd, 1H, H-2′,J=5.2, 11.2 Hz), 0.93 and 0.83 (2s, 18H, t-Bu), 0.12, 0.01, and 0.0.1(3s, 12H, SiCH₃). Resonances of the tetrazolyl form (<10%): δ 8.57 (s,1H, Ar—H), 4.70 (m, 1H, H-3′), 0.81 (s, 18H, t-Bu), 0.13, 0.04, and 0.03(3s, 12H, SiCH₃). HRMS calculated for C₂₅H₄₃N₇O₄Si₂Na [M+Na]⁺: 584.2807found: 584.2818.

Example 6 Typical Procedure for the Ligation Reactions of 2aO⁶-Allyl-2-(4-phenyl-1,2,3-triazol-1H-yl)-2′,3′,5′-tri-O-(tert-butyldimethylsilyl)inosine(3)

Azide 2a (492.0 mg, 0.711 mmol) and CuCl (14.0 mg. 0.2 mol %) weresuspended in 8 mL of t-BuOH/H₂O (1:1), and reaction mixture was flushedwith nitrogen gas. Phenyl acetylene (155 μL, 1.42 mmol) was added andthe heterogeneous mixture was stirred at room temperature until TLCrevealed no starting material (see Table 2 for reaction times). Thereaction mixture was diluted with CH₂Cl₂ and washed with water followedby brine. The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure. Chromatographic purification on a silica gel columnusing 20% EtOAc in hexanes afforded 461.0 mg (82% yield) of 3 as anoff-white foam. R_(f)(SiO₂/20% EtOAc in hexanes)=0.57. ¹H NMR (CDCl₃): δ8.74 (s, 1H, Ar—H), 8.50 (s, 1H, Ar—H), 7.96 (d, 2H, Ar—H, J=7.8 Hz),7.48 (t, 2H, Ar—H, J=7.3 Hz), 7.39 (t, 1H, Ar—H, J=7.3 Hz), 6.23-6.19(m, 1H, ═CH), 6.17 (d, 1H, H-1′, J=4.4 Hz), 5.57 (dd, 1H, ═CH_(trans),J=1.0, 17.2 Hz), 5.37 (d, 1H, ═CH_(cis), J=10.3 Hz), 5.26 (d, 2H, OCH₂,J=6.3 Hz), 4.55 (t, 1H, H-2′, J=4.4 Hz), 4.35 (t, 1H, H-3′, J=4.2 Hz),4.18 (br s, 1H, H-4′), 4.10 (dd, 1H, H-5′, J=3.4, 11.7 Hz), 3.84 (dd,1H, H-5′, J=2.0, 11.7 Hz), 0.97, 0.94, and 0.83 (3s, 27H, t-Bu), 0.18,0.16, 0.11, 0.10, −0.02, and −0.07 (6s, 18H, SiCH₃). ¹³C NMR (CDCl₃): δ160.4, 151.8, 147.8, 147.0, 141.5, 131.1, 129.6, 128.2, 127.8, 125.3,120.6, 119.6, 117.8, 88.1, 84.6, 75.8, 70.8, 68.2, 61.6, 25.5, 25.2,25.0, 17.9, 17.5, 17.2, −4.9, −5.2, −5.3, −5.9. HRMS calculated forC₃₉H₆₄N₇O₅Si₃ [M+H]⁺: 794.4271, found: 794.4281.

Example 7O⁶-Allyl-2-[4-(4-methylphenyl)-1,2,3-triazol-1H-yl]-2′,3′,5′-tri-O-(tert-butyldimethylsilyl)inosine(4)

Synthesized from 2a (413.0 mg, 0.597 mmol) and 4-ethynyltoluene (138 μL,1.19 mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 15% EtOAc in hexanes yielded 380.1 mg (79% yield) of 4 as awhite, foamy solid. R_(f)(SiO₂/20% EtOAc in hexanes)=0.60. ¹H NMR(CDCl₃): δ 8.70 (s, 1H, Ar—H), 8.50 (s, 1H, Ar—H), 7.85 (d, 2H, Ar—H,J=7.8 Hz), 7.30 (d, 2H, Ar—H, J=7.8 Hz), 6.25-6.17 (m, 1H, ═CH), 6.16(d, 1H, H-1′, J=4.4 Hz), 5.56 (dd, 1H, ═CH_(I)., J=1.0, 17.1 Hz), 5.37(dd, 1H, J=1.0, 10.1 Hz), 5.26 (d, 2H, OCH₂, J=6.3 Hz), 4.52 (t, 1H,H-2′, J=4.4 Hz), 4.35 (t, 1H, H-3′, J=4.2 Hz), 4.18 (q, 1H, H-4′, J=3.0Hz), 4.10 (dd, 1H, H-5′, J=3.4, 11.2 Hz), 3.84 (dd, 1H, H-5′, J=2.4,11.2 Hz), 2.41 (s, 3H, CH₃), 0.97, 0.94, and 0.83, (3s, 27H, t-Bu),0.18, 0.16, 0.11, 0.09, −0.02, and −0.06 (6s, 18H, SiCH₃). ¹³C NMR(CDCl₃): δ 161.0, 152.5, 148.6, 147.8, 142.2, 138.5, 131.9, 129.7,129.1, 126.0, 121.2, 119.8, 118.2, 88.8, 85.3, 76.6, 71.5, 68.9, 62.3,26.3, 26.0, 25.8, 21.4, 18.7, 18.2, 18.0, −4.1, −4.5, −4.6, −5.1. HRMScalculated for C₄₀H₆₆N₇O₅Si₃ [M+H]⁺: 808.4428, found: 808.4435.

Example 8O⁶-Allyl-2-[4-(4-methoxyphenyl)-1,2,3-triazol-1H-yl]-2′,3′,5′-tri-O-(tert-butyldimethylsilyl)inosine(5)

Synthesized from 2a (403.0 mg, 0.582 mmol) and 4-ethynylanisole (154 μL,1.16 mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 20% EtOAc in hexanes yielded 373.3 mg (78% yield) of 5 as awhite, foamy solid. R_(f)(SiO₂/20% EtOAc in hexanes)=0.46. ¹H NMR(CDCl₃): δ 8.66 (s, 1H, Ar—H), 8.55 (s, 1H, Ar—H), 7.88 (d, 2H, Ar—H,J=8.3 Hz), 7.00 (d, 2H, Ar—H, J=8.3 Hz), 6.22 (m, 1H, ═CH), 6.16 (d, 1H,H-1′, J=3.9 Hz), 5.56 (d, 1H, ═CH_(trans), J=17.1 Hz), 5.36 (d, 1H,═CH_(cis), J=10.3 Hz), 5.25 (d, 2H, OCH₂, J=5.7 Hz), 4.47 (br t, 1H,H-2′, J=3.9 Hz), 4.33 (t, 1H, H-3′, J=3.9 Hz), 4.18 (br s, 1H, H-4′),4.10 (dd, 1H, H-5′, J=2.9, 11.7 Hz), 3.86 (s, 3H, OCH₃), 3.83 (br d, 1H,H-5′, J=11.7 Hz), 0.96, 0.91, and 0.82 (3s, 27H, t-Bu), 0.18, 0.15,0.09, 0.079, −0.00, and −0.07 (6s, 18H, SiCH₃). ¹³C NMR (CDCl₃): δ161.2, 160.0, 152.6, 148.6, 147.6, 142.2, 131.9, 127.4, 123.01, 121.3,119.8, 117.7, 114.5, 88.7, 85.3, 76.6, 71.6, 68.9, 62.3, 55.5, 26.3,26.0, 25.8, 18.7, 18.2, 18.0, −4.1, −4.9, −4.5, −4.6, −5.1, −5.2. HRMScalculated for C₄₀H₆₆N₇O₆Si₃ [M+H]⁺: 824.4377, found: 824.4380.

Example 9O⁶-Allyl-2-[4-(hydroxymethyl-1,2,3-triazol-1H-yl]-2′,3′,5′-tri-O-(tert-butyldimethylsilyl)inosine(6)

Synthesized from 2a (368.0 mg, 0.532 mmol) and propargyl alcohol (61 pt,1.06 mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 40% EtOAc in hexanes yielded 311.3 mg (79% yield) of 6 as awhite, foamy solid. R_(f)(SiO₂/40% EtOAc in hexanes)=0.48. ¹H NMR(CDCl₃): δ 8.54 (s, 1H, Ar—H), 8.49 (s, 1H, Ar—H), 6.25-6.18 (m, 1H,═CH), 6.16 (d, 1H, H-1′, J=4.3 Hz), 5.56 (dd, 1H, ═CH_(trans), J=1.5,17.2 Hz), 5.38 (dd, 1H, ═CH_(cis), J=1.5, 10.3 Hz), 5.24 (d, 2H, OCH₂,J=5.6 Hz), 4.97 (s, 2H, CH₂), 4.58 (t, 1H, H-2′, J=4.2 Hz), 4.35 (t, 1H,H-3′, J=4.2 Hz), 4.19 (q, 1H, H-4′, J=3.6 Hz), 4.09 (dd, 1H, H-5′,J=3.6, 11.6 Hz), 3.85 (dd, 1H, H-5′, J=2.0, 11.6 Hz), 0.99, 0.96, and0.83 (3s, 27H, t-Bu), 0.20, 0.18, 0.13, 0.12, 0.02, and 0.11 (6s, 18H,SiCH₃). ¹³C NMR (CDCl₃): δ 161.1, 152.5, 148.5, 147.9, 142.4, 131.8,121.9, 121.1, 119.7, 88.8, 85.5, 76.5, 71.7, 68.9, 62.4, 56.6, 26.2,25.9, 25.7, 18.6, 18.2, 17.9, −4.1, −4.5, −4.6, −4.7, −5.2. HRMScalculated for C₃₄H₆₂N₇O₆Si₃ [M+H]⁺: 748.4064, found: 748.4064.

Example 10O⁶-Allyl-2-[4-(N-phthalimidomethyl)-1,2,3-triazol-1H-yl]-2′,3′,5′-tri-O-(tert-butyldimethylsilyl)inosine(7)

Synthesized from 2a (418 mg, 0.604 mmol) and N-propargyl phthalimide(223.0 mg, 1.20 mmol). Chromatography of the crude reaction mixture on asilica gel column using 20% EtOAc in hexanes yielded 435.3 mg (82%yield) of 7 as an off-white, foamy solid. R_(f)(SiO₂/20% EtOAc inhexanes)=0.44. ¹H NMR (CDCl₃): δ 8.53 (s, 1H, Ar—H), 8.49 (s, 1H, Ar-8),7.89 (dd, 2H, ArH, J=3.2, 5.4 Hz), 7.74 (dd, 2H, ArH, J=3.2, 5.4 Hz),6.22-6.14 (m, 1H, ═CH), 6.10 (d, 1H, H-1′, J=4.1 Hz), 5.56 (dd, 1H,═CH_(trans), J=1.2, 17.2 Hz), 5.35 (br d, 1H, ═CH_(cis), J=10.4 Hz),5.22 (d, 2H, OCH₂, J=5.9 Hz), 5.12 (s, 2H, NCH₂), 4.51 (t, 1H, H-2′,J=4.0 Hz), 4.34 (t, 1H, H-3′, J=4.0 Hz), 4.17 (app q, 1H, H-4′,J_(app)˜4.0 Hz), 4.10 (dd, 1H, H-5′, J=3.5, 11.6 Hz), 3.82 (dd, 1H,J=2.6, 11.6 Hz), 0.96, 0.93, and 0.81 (3s, 27H, t-Bu), 0.17, 0.15, 0.11,0.08, 0.00, and 0.10 (6s, 18H, SiCH₃). ¹³C NMR (CDCl₃): δ 167.6, 161.1,152.4, 148.4, 143.0, 142.3, 142.3, 134.2, 132.2, 123.6, 122.1, 121.2,119.8, 88.9, 85.2, 76.5, 71.4, 68.9, 62.2, 33.2, 26.2, 25.9, 25.7, 18.6,18.2, 17.9, −4.1, −4.6, −5.1, −5.2. HRMS calculated for C₄₂H₆₅N₈O₇Si₃[M+H]⁺: 877.4279, found: 877.4293.

Example 11O⁶-Allyl-2-(4-ferrocenyl-1,2,3-triazol-1H-yl)-2′,3′,5′-tri-O-(tert-butyldimethylsilyl)inosine(8)

Synthesized from 2a (482.0 mg, 0.697 mmol) and ethynylferrocene (292.0mg, 1.39 mmol). Chromatography of the crude reaction mixture on a silicagel column using 10% EtOAc in hexanes yielded 492.8 mg (78% yield) of 8as a brown, foamy solid. R_(f)(SiO₂/20% EtOAc in hexanes)=0.62. ¹H NMR(CDCl₃): δ 8.53 (s, 1H, Ar—H), 8.43 (s, 1H, Ar—H), 6.26-6.19 (m, 1H,═CH), 6.18 (d, 1H, H-1′, J=3.9 Hz), 5.58 (br d, 1H, ═CH_(trans), J=17.1Hz), 5.38 (br d, 1H, ═CH_(cis), J=10.4 Hz), 5.27 (d, 2H, OCH₂, J=5.8Hz), 4.84 (app q, 1H, ferrocenyl-H, J_(app)˜1.9 Hz), 4.82 (app q, 1H,ferrocenyl-H, J_(app)˜1.9 Hz), 4.52 (t, 1H, H-2′ J=4.3 Hz), 4.35 (d, 2H,ferrocenyl-H, J=1.9 Hz), 4.34 (t, 1H, H-3′, J=3.9 Hz), 4.18 (br s, 1H,H-4′), 4.12 (s, 5H, ferrocenyl-H), 4.09 (dd, 1H, H-5′, J=3.5, 11.5 Hz),3.84 (dd, 1H, H-5′, J=2.3, 11.5 Hz), 1.00, 0.96, and 0.87 (3s, 27H,t-Bu), 0.21, 0.19, 0.14, 0.12, 0.05, and −0.03 (6s, 18H, SiCH₃). ¹³C NMR(CDCl₃): δ 161.0, 152.4, 148.3, 146.9, 141.8, 131.8, 120.9, 119.7,117.2, 88.5, 85.1, 76.6, 74.7, 71.3, 69.5, 68.8, 68.7, 66.8, 62.1, 26.1,25.8, 25.6, 18.5, 18.0, 17.8, −4.3, −4.6, −4.7, −4.8, −5.3, −5.4 HRMScalculated for C₄₃H₆₈FeN₇O₅Si₃ [M+H]⁺: 902.3934, found: 902.3936.

Example 12O⁶-Allyl-2-(4-n-butyl-1,2,3-triazol-1H-yl)-2′,3′,5′-tri-O-(tert-butyldimethylsilyl)inosine(9)

Synthesized from 2a (595.0 mg, 0.860 mmol) and propargyl alcohol (197μL, 1.72 mmol). Chromatography of the crude reaction mixture on a silicagel column using 15% EtOAc in hexanes yielded 501.3 mg (75% yield) of 9as a white, foamy solid. R_(f)(SiO₂/20% EtOAc in hexanes)=0.48. ¹H NMR(CDCl₃): δ 8.48 (s, 1H, Ar—H), 8.26 (s, 1H, Ar—H), 6.25-6.17 (m, 1H,═CH), 6.16 (d, 1H, H-1′, J=4.3 Hz), 5.56 (dd, 1H, ═CH_(trans), J=1.4,17.2 Hz), 5.38 (dd, 1H, ═CH_(cis), J=1.4, 10.5 Hz), 5.25 (d, 2H, OCH₂,J=5.9 Hz), 4.54 (t, 1H, H-2′, J=4.2 Hz), 4.35 (t, 1H, H-3′, J=4.3 Hz),4.18 (app q, 1H, H-4′, J_(app)˜3.5 Hz), 4.09 (dd, 1H, H-5′, J=3.5, 11.5Hz), 3.84 (dd, 1H, H-5′, J=2.2, 11.5 Hz), 2.84 (t, 2H, butyl-CH₂, J=7.6Hz), 1.75 (quint, 2H, butyl-CH₂, J=7.6 Hz), 1.46 (sextet, 2H, butyl-CH₂,J=7.5 Hz), 0.99 (t, 3H, butyl-CHs, J=7.5 Hz), 0.98, 0.95, and 0.83 (3s,27H, t-Bu), 0.19, 0.17, 0.12, 0.11, −0.02, and −0.09 (6s, 18H, SiCH₃).¹³C NMR (CDCl₃): δ 161.3, 152.6, 148.8, 148.6, 142.2, 132.0, 121.2,120.1, 119.8, 88.9, 85.4, 76.7, 71.7, 69.0, 62.5, 31.6, 26.4, 26.1,25.9, 25.5, 22.5, 18.8, 18.3, 18.1, 14.0, −4.1, −4.4, −4.5, −4.6, −5.1.HRMS calculated for C₃₇H₆₈N₇O₅Si₃ [M+H]⁺: 774.4584, found: 774.4582.

Example 13O⁶-Allyl-2-[4-(4-fluorophenyl)-1,2,3-triazol-1H-yl]-2′,3′,5′-tri-O-(tert-butyldimethylsilyl)inosine(10)

Synthesized from 2a (600.0 mg, 0.867 mmol) and 4-ethynylfluorobenzene(200 μL, 1.73 mmol). Chromatography of the crude reaction mixture on asilica gel column using 15% EtOAc in hexanes yielded 500.1 mg (71%yield) of 10 as an off-white, foamy solid. R_(f)(SiO₂/20% EtOAc inhexanes)=0.61. ¹H NMR (CDCl₃): δ 8.70 (s, 1H, Ar—H), 8.52 (s, 1H, Ar—H),7.95 (dd, 2H, Ar—H, J=5.3, 8.6 Hz), 7.19 (t, 2H, Ar—H, J=8.6 Hz),6.27-6.19 (m, 1H, ═CH), 6.08 (d, 1H, H-1′, J=4.3 Hz), 5.57 (dd, 1H,═CH_(trans), J=1.0, 17.2 Hz), 5.39 (dd, 1H, ═CH_(cis), J=1.0, 10.4 Hz),5.29 (d, 2H, OCH₂, J=5.9 Hz), 4.57 (t, 1H, H-2′, J=4.2 Hz), 4.37 (t, 1H,H-3′, J=4.2 Hz), 4.20 (br s, 1H, H-4′), 4.11 (dd, 1H, H-5′, J=3.6, 11.6Hz), 3.82 (dd, 1H, H-5′, J=2.1, 11.6 Hz), 0.99, 0.96, and 0.85 (3s, 27H,t-Bu), 0.20, 0.18, 0.13, 0.12, 0.04, and −0.06 (6s, 18H, SiCH₃). ¹³C NMR(CDCl₃): δ 164.1 and 162.1 (d, ¹J=246.8 Hz), 161.2, 152.6, 148.5, 146.9,142.4, 131.9, 128.0 and 127.9 (d, ³J=8.2 Hz), 126.6, 121.4, 119.8,118.2, 116.2 and 116.0 (d, ²J=21.8 Hz), 88.8, 85.5, 76.7, 71.6, 69.0,62.4, 26.3, 26.0, 25.8, 18.7, 18.3, 18.0, −4.1, −4.4, −4.5, −4.6, −5.1.HRMS calculated for C₃₉H₆₂FN₇O₅Si₃Na [M+Na]⁺: 834.3996, found: 834.3993.

Example 14O⁶-Allyl-2-(4-phenyl-1,2,3-triazol-1H-yl)-3′,5′-di-O-(tert-butyldimethylsilyl)-2′-deoxyinosine(11)

Synthesized from 2b (320.0 mg, 0.569 mmol) and phenyl acetylene (125 μL,1.13 mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 30% EtOAc in hexanes yielded 281.2 mg (74% yield) of 11 asan off-white, foamy solid. R_(f)(SiO₂/20% EtOAc in hexanes)=0.50. ¹H NMR(CDCl₃): δ 8.76 (s, 1H, Ar—H), 8.41 (s, 1H, Ar—H), 7.99 (d, 2H, Ar—H,J=8.0 Hz), 7.49 (t, 2H, Ar—H, J=7.5 Hz), 7.40 (t, 1H, Ar—H, J=7.5 Hz),6.64 (t, 1H, H-1′, J=6.2 Hz), 6.26-6.19 (m, 1H, ═CH), 5.58 (d, 1H,═CH_(trans), J=17.2 Hz), 5.39 (d, 1H, ═CH_(cis), J=10.4 Hz), 5.27 (d,2H, OCH₂, J=5.3 Hz), 4.68 (br s, 1H, H-3′), 4.07 (m, 1H, H-4′), 3.95 (brd, 1H, H-5′, J=11.3 Hz), 3.79 (br d, 1H, H-5′, J=11.3 Hz), 2.62 (appquint, 1H, H-2′, J_(app)˜6.5 Hz), 2.58-2.54 (m, 1H, H-2′), 0.95 (s, 18H,t-Bu), 0.14 (s, 12H, SiCH₃). ¹³C NMR (CDCl₃): δ 161.1, 152.5, 148.5,147.9, 142.0, 131.9, 130.3, 129.0, 128.7, 126.2, 121.1, 119.8, 118.8,88.3, 84.7, 71.9, 69.0, 62.9, 42.2, 26.2, 25.9, 18.6, 18.2, −4.3, −4.5,−5.1, −5.2. HRMS calculated for C₃₃H₄₉N₇O₄Si₂Na [M+Na]⁺: 686.3277,found: 686.3285.

Example 15O⁶-Allyl-2-[4-(4-methoxyphenyl)-1,2,3-triazol-1H-yl]-3′,5′-di-O-(tert-butyldimethylsilyl)-2′-deoxyinosine(12)

Synthesized from 2b (352.0 mg, 0.626 mmol) and 4-ethynylanisole (165 μL,1.25 mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 40% EtOAc in hexanes yielded 302.3 mg (78% yield) of 12 asan off-white, foamy solid. R_(f)(SiO₂/30% EtOAc in hexanes)=0.54. ¹H NMR(CDCl₃): δ 8.67 (s, 1H, Ar—H), 8.42 (s, 1H, Ar—H), 7.91 (d, 2H, Ar—H,J=8.0 Hz), 7.02 (d, 2H, Ar—H, J=8.0 Hz), 6.64 (br s, 1H, H-1′), 6.17 (brm, 1H, ═CH), 5.58 (d, 1H, ═CH_(trans), J=17.0 Hz), 5.38 (d, 1H,═CH_(cis), J=10.3 Hz), 5.26 (br d, 2H, _(OCH2), J=4.6 Hz), 4.68 (br s,1H, H-3′), 4.06 (br s, 1H, H-4′), 3.94 (br d, 1H, H-5′, J=11.2 Hz), 3.88(s, 3H, OCH₃), 3.83 (br d, 1H, H-5′, J=11.2 Hz), 2.64-2.54 (br m, 2H,H-2′), 0.94 (s, 18H, t-Bu), 0.14 (s, 12H, SiCH₃). ¹³C NMR (CDCl₃):161.1, 160.0, 152.5, 148.6, 147.7, 142.1, 132.0, 127.5, 123.0, 121.2,119.7, 117.9, 114.5, 88.3, 84.7, 71.9, 68.9, 62.9, 55.5, 42.1, 26.1,25.9, 18.6, 18.2, −4.3, −4.5, −4.9, −5.3. HRMS calculated forC₃₄H₅₁N₇O₅Si₂Na [M+Na]⁺: 716.3382, found: 716.3395.

Example 16O⁶-Allyl-2-[4-(hydroxymethyl)-1,2,3-triazol-1H-yl]-3′,5′-di-O-(tert-butyldimethylsilyl)-2′-deoxyinosine(13)

Synthesized from 2b (350.0 mg, 0.622 mmol) and propargyl alcohol (272μL, 1.24 mmol). Chromatography of the crude reaction mixture on a silicagel column using 50% EtOAc in hexanes yielded 272.1 mg (70% yield) of 13as a white, foamy solid. R_(f)(SiO₂/40% EtOAc in hexanes)=0.21. ¹H NMR(CDCl₃): δ 8.55 (s, 1H, Ar—H), 8.40 (s, 1H, Ar—H), 6.59 (t, 1H, H-1′,J=6.3 Hz), 6.20-6.15 (m, 1H, ═CH), 5.52 (d, 1H, ═CH_(trans), J=17.2 Hz),5.34 (d, 1H, ═CH_(cis), J=10.4 Hz), 5.20 (d, 2H, OCH₂, J=5.9 Hz), 4.93(d, 2H, CH₂, J=5.9 Hz), 4.65 (app q, 1H, H-3′, J_(app)˜4.5 Hz), 4.02 (brd, 1H, H-4′ J=3.2 Hz), 3.91 (dd, 1H, H-5′, J=3.5, 11.5 Hz), 3.80 (dd,1H, H-5′, J=2.7, 11.3 Hz), 3.01 (t, 1H, OH, J=5.9 Hz), 2.60 (app quint,1H, H-2′, J_(app)˜6.5 Hz), 2.56-2.52 (ddd, 1H, H-2′ J=4.5, 6.0, 10.6Hz), 0.92 (s, 18H, t-Bu), 0.11 (s, 12H, SiCH₃). ¹³C NMR (CDCl₃): δ161.1, 152.4, 148.4, 148.0, 142.2, 131.9, 121.4, 121.2, 119.7, 88.3,84.7, 71.8, 68.9, 62.9, 56.8, 42.1, 26.1, 25.9, 18.6, 18.2, −4.4, −4.5,−5.1, −5.2. HRMS calculated for C₂₈H₄₇N₇O₅Si₂Na [M+Na]⁺: 640.3069,found: 640.3077.

Example 17O⁶-Allyl-2-[4-(N-phthalimidomethyl)-1,2,3-triazol-1H-yl]-3′,5′-di-O-(tert-butyldimethylsilyl)-2′-deoxyinosine(14)

Synthesized from 2b (365.0 mg, 0.649 mmol) and N-propargyl phthalimide(240 μL, 1.29 mmol). Chromatography of the crude reaction mixture on asilica gel column using 35% EtOAc in hexanes yielded 351.8 mg (73%yield) of 14 as a white, foamy solid. R_(f)(SiO₂/20% EtOAc inhexanes)=0.28. ¹H NMR (CDCl₃): δ 8.56 (s, 1H, Ar—H), 8.39 (s, 1H, Ar—H),7.88 (dd, 2H, Ar—H, J=3.0, 5.5 Hz), 7.74 (dd, 2H, Ar—H, J=3.0, 5.5 Hz),6.57 (t, 1H, H-1′, J=6.3 Hz), 6.21-6.13 (m, 1H, ═CH), 5.53 (dd, 1H, ═CH,J=1.4, 17.2 Hz), 5.34 (dd, 1H, ═CH_(cis), J=1.4, 10.4 Hz), 5.20 (d, 2H,OCH₂, J=5.9 Hz), 5.12 (s, 2H, NCH₂), 4.64 (app q, 1H, H-3′,J_(app)˜4.0), 4.02 (app q, 1H, H-4′, J_(app)˜3.3 Hz), 3.92 (dd, 1H,H-5′, J=3.5, 11.3 Hz), 3.80 (dd, 1H, H-5′, J=2.9, 11.3 Hz), 2.57 (appquint, 1H, H-2′, J_(app)˜6.5 Hz), 2.50 (ddd, 1H, H-2′, J=4.5, 6.3, 10.6Hz), 0.92 and 0.90 (2s, 18H, t-Bu), 0.12 and 0.10 (2s, 12H, SiCH₃). ¹³CNMR (CDCl₃): δ 167.5, 160.9, 152.1, 148.1, 142.8, 141.8, 134.1, 132.0,131.7, 123.4, 122.2, 119.5, 88.1, 84.5, 71.6, 68.7, 62.6, 58.1, 41.9,33.0, 25.9, 25.7, 18.4, 18.0, −4.6, −4.8, −5.3, −5.5. HRMS calculatedfor C₃₆H₅₀N₈O₆Si₂Na [M+Na]⁺: 769.3284, found: 769.3290.

Example 18O⁶-Allyl-2-(4-ferrocenyl-1,2,3-triazol-1H-yl)-3′,5′-di-O-(tert-butyldimethylsilyl)-2′-deoxyinosine(15)

Synthesized from 2b (595.0 mg, 1.05 mmol) and ethynylferrocene (444 μL,2.11 mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 20% EtOAc in hexanes yielded 620.2 mg (72% yield) of 15 asa reddish-brown, foamy solid. R_(f)(SiO₂/30% EtOAc in hexanes)=0.30. ¹HNMR (CDCl₃): δ 8.40 (s, 1H, Ar—H), 8.35 (s, 1H, Ar—H), 6.64 (br s, 1H,H-1′), 6.23 (br m, 1H, ═CH), 5.57 (d, 1H, ═CH_(t), J=17.0 Hz), 5.40 (d,1H, ═CH_(cis), J=10.0 Hz), 5.26 (br s, 2H, OCH₂), 5.04 (br s, 2H,ferrocenyl-H), 4.66 (br s, 1H, H-3′), 4.54 (br s, 2H, ferrocenyl-H),4.28 (br s, 5H, ferrocenyl-H), 4.06 (br s, 1H, H-4′), 3.93 (dd, 1H, H5′,J=3.0, 11.2 Hz), 3.82 (dd, 1H, H-5′, J=2.0, 11.2 Hz), 2.59-2.57 (br m,2H, H-2′), 0.95 and 0.94 (2s, 18H, t-Bu), 0.14 and 0.13 (2s, 12H,SiCH₃). ¹³C NMR (CDCl₃) δ 161.2, 152.6, 148.7, 147.3, 142.0, 132.1,121.1, 119.8, 117.7, 88.4, 84.6, 72.0, 69.8, 69.1, 69.0, 67.2, 67.1,63.0, 42.3, 26.2, 26.0, 18.7, 18.3, −4.4, −4.6, −5.1, −5.3. HRMScalculated for C₃₇H₅₄FeN₇O₄Si₂ [M+H]⁺: 772.3120, found: 772.3126.

Example 19O⁶-Allyl-2-(4-n-butyl-1,2,3-triazol-1H-yl)-3′,5′-di-O-(tert-butyldimethylsilyl)-2′-deoxyinosine(16)

Synthesized from 2b (393.0 mg, 0.699 mmol) and 1-hexyne (160 μL, 1.39mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 20% EtOAc in hexanes yielded 320.1 mg (71% yield) of 16 asa white, foamy solid. R_(f)(SiO₂/20% EtOAc in hexanes)=0.40. ¹H NMR(CDCl₃): δ 8.41 (s, 1H, Ar—H), 8.28 (s, 1H, Ar—H), 6.62 (t, 1H, H-1′,J=6.3 Hz), 6.23-6.15 (m, 1H, ═CH), 5.53 (dd, 1H, ═CH_(trans), J=1.4,17.2 Hz), 5.36 (dd, 1H, ═CH_(cis), J=1.4, 10.4 Hz), 5.22 (d, 2H, OCH₂,J=5.9 Hz), 4.64 (m, 1H, H-3′), 4.02 (app q, 1H, H-4′, J_(app)˜3.5 Hz),3.92 (dd, 1H, H-5′, J=3.4, 11.3 Hz), 3.81 (dd, 1H, H-5′, J=2.7, 11.3Hz), 2.83 (t, 2H, butyl-CH₂, J=7.7 Hz), 2.57 (app quint, 1H, H-2′,J_(app)˜6.5 Hz), 2.52 (ddd, 1H, H-2′, J=4.3, 6.3, 11.0 Hz), 1.74 (quint,2H, butyl-CH₂, J=7.5 Hz), 1.44 (sextet, 2H, butyl-CH₂, J=7.5 Hz), 0.96(t, 3H,butyl-CH₃, J=7.5 Hz), 0.93 and 0.92 (2s, 18H, t-Bu), 0.12 and0.11 (2s, 12H, SiCH₃). ¹³C NMR (CDCl₃): δ 160.9, 152.3, 148.6, 1485,141.9, 131.8, 120.9, 120.0, 119.5, 88.1, 84.5, 71.7, 68.7, 62.8, 41.9,31.5, 26.0, 25.8, 25.3, 22.3, 18.5, 18.0, 13.8, −4.5, −4.7, −5.3, −5.4.

HRMS calculated for C₃₁H₅₄N₇O₄Si₂ [M+H]⁺: 644.3770, found: 644.3777.

Example 20 Typical Procedure for Disilylation and Deallylation Reactionsof the Triazolyl Nucleosides 2-[4-(Phenyl)-1,2,3-triazol-1H-yl]inosine(17) Step 1: Disilylation.

Et₃N.3HF (389 μL, 2.39 mmol) was added to a solution of 3 (380.0 mg,0.47 mmol) in dry THF (5.0 mL), and the reaction mixture was stirred atroom temperature for 24 h. The mixture was evaporated under a stream ofnitrogen gas using a polypropylene pipet. The crude product was purifiedby chromatography on silica gel column using 10% MeOH in EtOAc to give171.2 mg (80% yield) of the O⁶-allyl-protected nucleoside as colorless,amorphous solid. R_(f)(SiO₂/10% MeoH in EtOAc)=0.31. ¹H NMR (DMSO-d₆): δ9.42 (s, 1H, Ar—H), 8.74 (s, 1H, Ar—H), 8.00 (d, 2H, Ar—H, J=8.3 Hz),7.52 (t, 2H, Ar—H, J=7.5 Hz), 7.43 (t, 1H, Ar—H, J=7.5 Hz), 6.26-6.15(m, 1H, ═CH), 6.08 (d, 1H, H-1′, J=5.8 Hz), 5.64 (br s, 1H, OH), 5.56(dd, 1H, ═CH_(trans), J=1.6, 17.2 Hz), 5.39 (br d, 1H, ═CH_(cis), J=17.2Hz), 5.37 (br s, 1H, OH), 5.28 (d, 2H, OCH₂, J=5.8 Hz), 5.11 (t, 1H, OH,J=5.3 Hz), 4.66 (br s, 1H, H-2′), 4.23 (br s, 1H, H-3′), 4.01 (app q,1H, H-4′, J_(app)˜3.6 Hz), 3.71 (ddd, 1H, H-5′, J=2.8, 7.2, 11.2 Hz),3.63 (ddd, 1H, H-5′, J=5.0, 7.2, 11.2 Hz).

Step 2: Deallylation.

A solution of PhSO₂Na (14.5 mg, 0.088 mmol) in MeOH (1.0 mL) was addedto a suspension of the desilylated product obtained in step 1 (40.0 mg,0.088 mmol) and Pd(PPh₃)₄ (5.1 mg, 5 mol %) in dry THF (2.0 mL), at roomtemperature. The reaction mixture was stirred at room temperature for 2h at which time TLC revealed no starting material. The reaction mixturewas concentrated under reduced pressure and triturated with EtOAc togive 26.4 mg (72% yield) of 17 as a white solid. R_(f)(SiO₂/MeOH)=0.54.¹H NMR (DMSO-d₆): δ 9.07 (s, 1H, Ar—H), 8.01 (s, 1H, Ar—H), 7.98 (d, 2H,Ar—H, J=7.8 Hz), 7.48 (t, 2H, Ar—H, J=7.3 Hz), 7.36 (t, 1H, Ar—H, J=7.3Hz), 5.86 (d, 1H, H-1′, J=6.3 Hz), 5.46 (d, 1H, OH, J=6.3 Hz), 5.20 (d,1H, OH, J=4.6 Hz), 5.08 (t, 1H, OH, J=6.0 Hz), 4.66 (app q, 1H, H-2′,J_(app)˜5.9 Hz), 4.19 (app q, 1H, H-3′, J_(app)˜4.0 Hz), 3.95 (q, 1H,H-4′, J=3.4 Hz), 3.71-3.66 (m, 1H, H-5′), 3.59-3.54 (m, 1H, H-5′). ¹³CNMR (DMSO-d₆): δ 167.8, 151.5, 150.6, 147.4, 137.8, 131.9, 129.6, 128.8,126.0, 125.5, 120.6, 87.9, 86.2, 73.9, 71.4, 62.5. HRMS calculated forC₁₈H₁₇N₇O₅Na [M+Na]⁺: 434.1183, found: 434.1200.

Example 21 2-[4-(4-Methylphenyl)-1,2,3-triazol-1H-yl]inosine (18) Step1: Desilylation.

Using the procedure described for the desilylation of 17, this compoundwas synthesized from 4 (300.0 mg, 0.371 mmol) and Et₃N.3HF (300 μL, 1.85mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 10% MeOH in EtOAc yielded 130.8 mg (76% yield) of theO⁶-allyl-protected nucleoside as a white, foamy solid. R_(f)(SiO₂/10%MeOH in EtOAc)=0.27. ¹H NMR (DMSO-d6): δ 9.37 (s, 1H, Ar—H), 8.74 (s,1H, Ar—H), 7.95 (d, 2H, Ar—H, J=7.9 Hz), 7.32 (d, 2H, Ar—H, J=7.9 Hz),6.26-6.18 (m, 1H, ═CH), 6.08 (d, 1H, H-1′, J=5.8 Hz), 5.57 (d, 1H, OH,J=5.4 Hz), 5.56 (br s, 1H, ═CH_(trans), 5.38 (d, 1H, ═CH_(cis), J=10.5Hz), 5.31 (d, 1H, OH, J=5.6 Hz), 5.28 (d, 2H, OCH₂, J=5.7 Hz), 5.04 (t,1H, OH, J=5.5 Hz), 4.66 (app q, 1H, H-2′, J_(app)˜5.5 Hz), 4.22 (app q,1H, H-3′, J_(app)˜4.0 Hz), 4.00 (br d, 1H, H-4′, J=3.5 Hz), 3.74-3.69(m, 1H, H-5′), 3.63-3.59 (m, 1H, H-5′), 2.36 (s, 3H, CH₃).

Step 2: Deallylation.

The desilylated product (80.0 mg, 0.172 mmol) obtained in step 1 wasdeallylated as described for 17 using Pd(PPh₃)₄ (5.1 mg, 5 mol %) andPhSO₂Na (26.9 mg, 0.172 mmol) to yield 52.2 mg (71% yield) of 18 as apale yellow solid. R_(f)(SiO₂/MeOH)=0.64. ^(1H) NMR (DMSO-d6): δ 8.95(s, 1H, Ar—H), 7.95 (s, 1H, Ar—H), 7.87 (d, 2H, Ar—H, J=8.0 Hz), 7.28(d, 2H, Ar—H, J=8.0 Hz), 5.82 (d, 1H, H-1′, J=6.3 Hz), 5.41 (d, 1H, OH,J=6.3 Hz), 5.12 (d, 1H, OH, J=4.6 Hz), 5.04 (t, 1H, OH, J=5.6 Hz), 4.65(app q, 1H, H-2′, J_(app)˜6.0 Hz), 4.15 (app q, 1H, H-3′, J_(app)˜4.5Hz), 4.00 (app q, 1H, H-4′, J_(app)˜3.7 Hz), 3.69-3.64 (m, 1H, H-5′),3.57-3.52 (m, 1H, H-5′), 2.34 (s, 3H, CH₃). ¹³C NMR (DMSO-d₆): δ 167.4,150.9, 150.1, 146.2, 137.6, 137.4, 129.8, 128.2, 125.7, 123.9, 119.5,87.6, 85.9, 73.6, 71.1, 61.2, 21.3. HRMS calculated for C₁₉H₁₉N₇O₅Na[M+Na]⁺: 448.1340, found: 448.1342.

Example 22 2-[4-(4-Methoxyphenyl)-1,2,3-triazol-1H-yl]inosine (19) Step1: Desilylation.

Using the procedure described for the desilylation of 17, this compoundwas synthesized from 5 (290.0 mg, 0.351 mmol) and Et₃N.3HF (285 μL, 1.75mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 10% MeOH in EtOAc yielded 135.0 mg (80% yield) of theO⁶-allyl-protected nucleoside as a white, foamy solid. R_(f)(SiO₂/5%MeOH in EtOAc)=0.19. ¹H NMR (DMSO-d6): δ 9.32 (s, 1H, Ar—H), 8.75 (s,1H, Ar—H), 7.95 (d, 2H, Ar—H, J=8.6 Hz), 7.00 (d, 2H, Ar—H, J=8.6 Hz),6.26-6.18 (m, 1H, ═CH), 6.07 (d, 1H, H-1′, J=5.7 Hz), 5.56 (dd, 1H,═CH_(trans), J=1.1, 17.2 Hz), 5.37 (dd, 1H, ═CH_(cis), J=1.1, 10.4 Hz),5.28 (d, 2H, OCH₂, J=5.5 Hz), 4.63 (t, 1H, H-2′, J=5.2 Hz), 4.23 (app t,1H, H-3′, J_(app)˜4.2 Hz), 4.17 (app q, 1H, H-4′, J_(app)˜3.8), 3.82 (s,3H, OCH₃), 3.70 (dd, 1H, H-5′, J=4.2, 12.0 Hz), 3.60 (dd, 1H, H-5′,J=4.0, 12.0 Hz).

Step 2: Deallylation.

The desilylated product (94.0 mg, 0.195 mmol) obtained in step 1 wasdeallylated as described for 17 using Pd(PPh₃)₄ (11.2 mg, 5 mol %) andPhSO₂Na (31.9 mg, 0.195 mmol) to yield 72.1 mg (84% yield) of 19 as awhite solid. R_(f)(SiO₂/MeOH)=0.73. ¹H NMR (DMSO-d6): δ 8.94 (s, 1H,Ar—H), 8.01 (s, 1H, Ar—H), 7.99 (d, 2H, Ar—H, J=8.7 Hz), 7.04 (d, 2H,Ar—H, J=8.7 Hz), 5.85 (d, 1H, H-1′, J=6.3 Hz), 5.46 (d, 1H, OH, J=6.3Hz), 5.19 (d, 1H, OH, J=4.6 Hz), 5.11 (t, 1H, OH, J=6.3 Hz), 4.64 (appq, 1H, H-2′, J_(app)˜5.8 Hz), 4.17 (app q, 1H, H-3′, J_(app)˜4.1 Hz),3.94 (app q, 1H, H-4′, J_(app)˜3.5 Hz), 3.80 (s, 3H, OCH₃), 3.71-3.65(m, 1H, H-5′), 3.59-3.53 (m, 1H, H-5′). ¹³C NMR (DMSO-d6): δ 167.1,159.7, 150.4, 146.2, 137.4, 127.4, 124.9, 124.0, 119.3, 115.0, 94.7,87.9, 86.2, 73.9, 71.4, 62.5, 55.8. HRMS calculated for C₁₉H₁₉N₇O₆Na[M+Na]⁺: 464.1289, found: 464.1299.

Example 23 2-[4-(Hydroxymethyl)-1,2,3-triazol-1H-yl]inosine (20) Step 1:Desilylation.

Using the procedure described for the desilylation of 17, this compoundwas synthesized from 6 (210.0 mg, 0.280 mmol) and Et₃N.3HF (228 μL, 1.40mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 10% MeOH in EtOAc yielded 95.0 mg (83% yield) of theO⁶-allyl-protected nucleoside as a white, foamy solid. R_(f)(SiO₂/10%MeOH in EtOAc)=0.46. ¹H NMR (DMSO-d6): δ 8.77 (s, 1H, Ar—H), 8.74 (s,1H, Ar—H), 6.24-6.16 (m, 1H, ═CH), 6.05 (d, 1H, H-1′, J=5.7 Hz), 5.58(d, 1H, OH, J=5.9 Hz), 5.53 (br d, 1H, ═CH_(trans), J=17.2 Hz), 5.39 (d,1H, OH, J=6.2 Hz), 5.36 (br d, 1H, ═CH_(cis), J=10.3 Hz), 5.30 (d, 1H,OH, J=4.9 Hz), 5.24 (d, 2H, OCH₂, J=5.9 Hz), 5.04 (t, 1H, OH, J=5.3 Hz),4.66-4.63 (m, 3H, CH₂ and H-2′), 4.22 (app q, 1H, H-3′, J_(app)˜4.5 Hz),3.99 (app q, 1H, H-4′, J_(app)˜4.0 Hz), 3.73-3.68 (m, 1H, H-5′),3.62-3.58 (m, 1H, H-5′).

Step 2: Deallylation.

The desilylated product (35.2 mg, 0.085 mmol) obtained in step 1 wasdeallylated as described for 17 using Pd(PPh₃)₄ (4.9 mg, 5 mol %) andPhSO₂Na (14.0 mg, 0.085 mmol) to yield 20.4 mg (64% yield) of 20 as awhite solid. R_(f)(SiO₂/MeOH)=0.54. ¹H NMR (DMSO-d₆): δ 8.43 (s, 1H,Ar—H), 7.97 (s, 1H, Ar—H), 5.83 (d, 1H, H-1′, J=5.8 Hz), 5.42 (d, 1H,OH, J=6.2 Hz), 5.23 (t, 1H, OH, J=5.8 Hz), 5.15 (d, 1H, OH, J=4.8 Hz),5.06 (t, 1H, OH, J=5.8 Hz), 4.63 (q, 1H, H-2′, J=5.9 Hz), 4.58 (d, 2H,CH₂, J=5.4 Hz), 4.15 (m, 1H, H-3′), 3.92 (m, 1H, H-4′), 3.67-3.62 (dt,1H, H-5′, J=4.4, 11.7 Hz), 3.56-3.51 (ddd, 1H, H-5′, J=4.4, 6.3, 11.2Hz). ¹³C NMR (DMSO-d₆): δ 166.9, 150.9, 150.1, 147.8, 137.0, 124.5,121.4, 87.6, 85.8, 73.6, 71.1, 62.2, 55.4. HRMS calculated forC₁₃H₁₅N₇O₆Na [M+Na]⁺: 388.0976, found: 388.0982.

Example 24 2-[4-(N-Phthalimidomethyl)-1,2,3-triazol-1H-yl]inosine (21)Step 1: Desilylation.

Using the procedure described for the desilylation of 17, this compoundwas synthesized from 7 (350.0 mg, 0.428 mmol) and Et₃N.3HF (348 μL, 2.14mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 10% MeOH in EtOAc yielded 165.0 mg (72% yield) of theO⁶-allyl-protected nucleoside as a white, foamy solid.R_(f)(SiO₂/EtOAc)=0.23. ¹H NMR (DMSO-d₆): δ 8.90 (s, 1H, Ar—H), 8.73 (s,1H, Ar—H), 7.93 (dd, 2H, Ar—H, J=3.2, 5.4 Hz), 7.74 (dd, 2H, Ar—H,J=3.2, 5.4 Hz), 6.22-6.14 (m, 1H, ═CH), 6.03 (d, 1H, H-1′, J=5.8 Hz),5.56 (d, 1H, OH, J=6.2 Hz), 5.53 (br d, 1H, ═CH_(trans), J=17.5 Hz),5.35 (d, 1H, ═CH_(cis), J=10.5 Hz), 5.28 (d, 1H, OH, J=5.0 Hz), 5.22 (d,2H, OCH₂, J=5.6 Hz), 5.02 (t, 1H, OH, J=5.4 Hz), 4.97 (s, 2H, NCH₂),4.62 (app q, 1H, H-2′ J_(app)˜5.5 Hz), 4.20 (app q, 1H, H-3′,J_(app)˜4.5 Hz), 3.98 (app q, 1H, H-4′, J_(app)˜4.1 Hz), 3.71-3.66 (m,1H, H-5′), 3.60-3.56 (m, 1H, H-5′).

Step 2: Deallylation.

The desilylated product (150.0 mg, 0.280 mmol) obtained in step 1 wasdeallylated as described for 17 using Pd(PPh₃)₄ (16.2 mg, 5 mol %) andPhSO₂Na (45.9 mg, 0.128 mmol) to yield 110.0 mg (79% yield) of 21 as awhite solid. R_(f)(SiO₂/MeOH)=0.70. ¹H NMR (DMSO-d6): δ 8.53 (s, 1H,Ar—H), 7.97 (s, 1H, Ar—H), 7.92 (dd, 2H, Ar—H, J=3.2, 5.4 Hz), 7.864(dd, 2H, Ar—H, J=3.2, 5.4 Hz), 5.80 (d, 1H, H-1′, J=6.3 Hz), 5.40 (d,1H, OH, J=6.3 Hz), 5.13 (d, 1H, OH, J=4.6 Hz), 5.03 (t, 1H, OH, J=5.9Hz), 4.91 (s, 2H, NCH₂), 4.60 (app q, 1H, H-2′, J_(app)˜5.6 Hz), 4.13(app q, 1H, H-3′, J_(app)˜4.7 Hz), 3.90 (app q, 1H, H-4′, J_(app)˜3.4Hz), 3.65-3.10 (m, 1H, H-5′), 3.53-3.48 (m, 1H, H-5′). ¹³C NMR(DMSO-d6): δ 167.8, 166.3, 150.4, 150.0, 142.2, 137.2, 134.9, 132.1,124.5, 123.6, 122.1, 87.6, 85.9, 73.7, 71.1, 62.2, 33.3. HRMS calculatedfor C₂₁H₁₉N₈O₇ [M+H]⁺: 495.1371, found: 495.1379.

Example 25 2-[4-(Ferrocenyl)-1,2,3-triazol-1H-yl]inosine (22) Step 1:Desilylation.

Using the procedure described for the desilylation of 17, this compoundwas synthesized from 8 (400.0 mg, 0.442 mmol) and Et₃N.3HF (359 μL, 2.21mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 10% MeOH in EtOAc yielded 175.0 mg (65% yield) of theO⁶-allyl-protected nucleoside as a brown, foamy solid. R_(f)(SiO₂/5%MeOH in EtOAc)=0.20. ¹H NMR (DMSO-d₆): δ 8.94 (s, 1H, Ar—H), 8.69 (s,1H, Ar—H), 6.21-6.13 (m, 1H, ═CH), 6.02 (d, 1H, H-1′, J=5.7 Hz), 5.53(br s, 1H, OH), 5.52 (br d, 1H, ═CH_(trans), J=17.0 Hz), 5.33 (d, 1H,═CH_(cis), J=10.3 Hz), 5.27 (s, 1H, OH), 5.23 (d, 2H, OCH₂, J=5.6 Hz),5.00 (t, 1H, OH, J=4.3 Hz), 4.88 (s, 2H, ferrocenyl-H), 4.60 (br t, 1H,H-2′, J=4.5 Hz), 4.33 (s, 2H, ferrocenyl-H), 4.10 (br s, 1H, H-3′), 4.04(s, 5H, ferrocenyl-H), 3.95 (br s, 1H, H-4′), 3.67-3.65 (m, 1H, H-5′),3.57-3.55 (m, 1H, H-5′).

Step 2: Deallylation.

The desilylated product (95.0 mg, 0.156 mmol) obtained in step 1 wasdeallylated as described for 17 using Pd(PPh₃)₄ (9.0 mg, 5 mol %) andPhSO₂Na (25.6 mg, 0.156 mmol) to yield 70.1 mg (86% yield) of 22 as abrown red solid. R_(f)(SiO₂/MeOH)=0.71. ¹H NMR (DMSO-d₆): δ 8.66 (s, 1H,Ar—H), 7.99 (s, 1H, Ar—H), 5.84 (d, 1H, H-1′, J=6.3 Hz), 5.46 (br s, 1H,OH), 5.20 (br s, 1H, OH), 5.09 (t, 1H, OH, J=5.3 Hz), 4.86 (s, 2H,ferrocenyl-H), 4.63 (br s, 1H, H-2′), 4.33 (s, 2H, ferrocenyl-H), 4.17(br s, 1H, H-3′), 4.07 (s, 5H, ferrocenyl-H), 3.94 (br s, 1H, H-4′),3.69-3.66 (m, 1H, H-5′), 3.57-3.54 (m, 1H, H-5′). ¹³C NMR (DMSO-d₆): δ166.9, 150.8, 150.2, 145.2, 137.1, 124.5, 118.9, 87.5, 85.9, 79.6, 76.2,73.7, 71.2, 69.7, 68.7, 66.8, 62.2. HRMS calculated for C₂₂H₂₂FeN₇O₅[M+H]⁺: 520.1026, found: 520.1006.

Example 26 2-(4-n-Butyl-1,2,3-triazol-1H-yl)inosine (23) Step 1:Desilylation.

Using the procedure described for the desilylation of 17, this compoundwas synthesized from 9 (172.0 mg, 0.222 mmol) and Et₃N.3HF (180 μL, 1.10mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 10% MeOH in EtOAc yielded 70.1 mg (73% yield) of theO⁶-allyl-protected nucleoside as a white, foamy solid. R_(f)(SiO₂/10%MeOH in EtOAc)=0.57. ¹H NMR (DMSO-d₆): δ 8.73 (s, 1H, Ar—H), 8.69 (s,1H, Ar—H), 6.23-6.16 (m, 1H, ═CH), 6.05 (d, 1H, H-1′, J=5.7 Hz), 5.65(s, 1H, OH), 5.53 (dd, 1H, ═CH_(trans), J=1.2, 17.2 Hz), 5.36 (dd, 1H,═CH_(cis), J=1.2, 10.2 Hz), 5.24 (d, 2H, OCH₂, J=5.7 Hz), 5.07 (s, 1H,OH), 4.64 (t, 1H, H-2′, J=5.0 Hz), 4.23 (t, 1H, H-3′, J=3.8 Hz), 4.00(app q, 1H, H-4′, J_(app)˜4.0 Hz), 3.70 (br d, 1H, H-5′, J=10.2 Hz),3.60 (br d, 1H, H5′, J=10.2 Hz), 2.74 (t, 2H, butyl-CH₂, J=7.6 Hz), 1.68(quint, 2H, butyl-CH₂, J=7.6 Hz), 1.37 (sextet, 2H, butyl-CH₂, J=7.3Hz), 0.93 (t, 3H, butyl-CHs, J=7.3 Hz). ¹³C NMR (DMSO-d₆): δ 160.7,153.2, 148.1, 143.7, 132.8, 121.3, 120.6, 119.5, 87.9, 86.2, 74.2, 70.7,68.4, 61.6, 31.3, 24.3, 24.8, 22.0, 14.0.

Step 2: Deallylation.

The desilylated product (30.0 mg, 0.069 mmol) obtained in step 1 wasdeallylated as described for 17 using Pd(PPh₃)₄ (4.0 mg, 5 mol %) andPhSO₂Na (11.4 mg, 0.069 mmol) to yield 19.4 mg (70% yield) of 23 as awhite solid. R_(f)(SiO₂/MeOH)=0.51. ¹H NMR (DMSO-d₆): δ 8.32 (s, 1H,Ar—H), 7.96 (s, 1H, Ar—H), 5.82 (d, 1H, H-1′, J=6.3 Hz), 5.43 (d, 1H₂OH,J=6.2 Hz), 5.16 (d, 1H, OH, J=3.9 Hz), 5.07 (t, 1H, OH, J=5.8 Hz), 4.63(app q, 1H, H-2′, J_(app)˜5.9 Hz), 4.15 (app q, 1H, H-3′, Tapp 4.3 Hz),3.92 (app q, 1H, H-4′, J_(app)˜3.4 Hz), 3.67-3.63 (m, 1H, H-5′),3.56-3.51 (m, 1H, H-5′), 2.69 (t, 2H, butyl-CH₂, J=7.6 Hz), 1.64 (quint,2H, butyl-CH₂, J=7.5 Hz), 1.36 (sextet, 2H, butyl-CH₂, J=7.5 Hz), 0.92(t, 3H, butyl-CHs, J=7.3 Hz). ¹³C NMR (DMSO-d₆): δ 166.9, 150.9, 150.2,146.8, 137.1, 124.4, 120.6, 87.6, 85.9, 73.7, 71.1, 62.2, 31.4, 25.0,22.0, 14.1. HRMS calculated for C₁₆H₂₁N₇O₅Na [M+Na]⁺: 414.1496, found:414.1499.

Example 27 2-[4-(4-Fluorophenyl)-1,2,3-triazol-1H-yl]inosine (24) Step1: Desilylation.

Using the procedure described for the desilylation of 17, this compoundwas synthesized from 10 (310.0 mg, 0.381 mmol) and Et₃N.3HF (310 μL,1.90 mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 10% MeOH in EtOAc yielded 143.8 mg (80% yield) of theO⁶-allyl-protected nucleoside as a white, foamy solid. R_(f)(SiO₂/10%MeOH in EtOAc)=0.48. ¹H NMR (DMSO-d₆): δ 9.45 (s, 1H, Ar—H), 8.77 (s,1H, Ar—H), 8.11 (dd, 2H, Ar—H, J=5.3, 8.6 Hz), 7.36 (t, 2H, Ar—H, J=8.6Hz), 6.26-6.20 (m, 1H, ═CH), 6.18 (d, 1H, H-1′, J=5.8 Hz), 5.66 (br s,1H, OH), 5.57 (dd, 1H, ═CH_(trans), J=1.5, 17.2 Hz), 5.43 (br s, 1H,OH), 5.39 (dd, 1H, ═CH_(cis), J=1.2, 10.4 Hz), 5.29 (d, 2H, OCH₂, J=5.9Hz), 5.08 (t, 1H, OH, J=4.0 Hz), 4.68 (t, 1H, H-2′, J=5.2 Hz), 4.24 (t,1H, H-3′, J=3.9 Hz), 4.01 (app q, 1H, H-4′, J_(app)˜4.0 Hz), 3.74 (dd,1H, H-5′, J=4.2, 11.8 Hz), 3.62 (dd, 1H, H-5′, J=3.4, 11.8 Hz).

Step 2: Deallylation.

The desilylated product (24.0 mg, 0.048 mmol) obtained in step 1 wasdeallylated as described for 17 using Pd(PPh₃)₄ (2.8 mg, 5 mol %) andPhSO₂Na (8.0 mg, 0.048 mmol) to yield 15.0 mg (72% yield) of 24 as awhite solid. R_(f)(SiO₂/MeOH)=0.42. ¹H NMR (DMSO-d₆): δ 9.12 (s, 1H,Ar—H), 8.05 (s, 1H, Ar—H), 8.03 (br t, 2H, Ar—H, J_(app)˜6.8 Hz), 7.31(t, 2H, Ar—H, J=8.5 Hz), 5.87 (d, 1H, H-1′, J=6.2 Hz), 5.54 (br d, 1H,OH, J=4.6 Hz), 5.28 (br s, 1H, OH), 5.10 (t, 1H, OH, J=5.5 Hz), 4.66 (brd, 1H, H-2′, J=4.5 Hz), 4.18 (br s, 1H, H-3′), 3.94 (br s, 1H, H-4′),3.69-3.66 (m, 1H, H-5′), 3.57-3.54 (m, 1H, H-5′). ¹³C NMR (DMSO-d₆): δ167.1, 163.2 and 161.3 (d, ¹J=244.6 Hz), 150.8, 150.2, 145.2, 137.4,127.9 and 127.8 (d, ³J=8.2 Hz), 127.6, 124.5, 120.0, 116.3 and 116.1 (d,²J=21.5 Hz), 87.6, 86.0, 73.7, 71.1, 62.2. HRMS calculated forC₁₈H₁₆FN₇O₅Na [M+Na]⁺: 452.1089, found: 452.1090.

Example 28 2-[4-(Phenyl)-1,2,3-triazol-1H-yl]-2′-deoxyinosine (25) Step1: Desilylation.

Using the procedure described for the desilylation of 17, this compoundwas synthesized from 11 (230.0 mg, 0.346 mmol) and Et₃N.3HF (187 FAL,1.15 mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 8% MeOH in EtOAc yielded 120.1 mg (76% yield) of theO⁶-allyl-protected nucleoside as a white, foamy solid. R_(f)(SiO₂/10%MeOH in EtOAc)=0.50. ¹H NMR (DMSO-d6): δ 9.44 (s, 1H, Ar—H), 8.72 (s,1H, Ar—H), 8.07 (d, 2H, Ar—H, J=7.8 Hz), 7.51 (t, 2H, Ar—H, J=7.5 Hz),7.41 (t, 1H, Ar—H, J=7.5 Hz), 6.51 (t, 1H, H-1′, J=6.4 Hz), 6.26-6.18(m, 1H, ═CH), 5.56 (br d, 1H, ═CH_(trans), J=17.2 Hz), 5.38 (br d, 1H,═CH_(cis) J=10.4 Hz), 5.28 (d, 2H, OCH₂, J=5.9 Hz), 4.49 (br s, 1H,H-3′), 3.91 (br d, 1H, H-4′, J=2.5 Hz), 3.67 (dd, 1H, H-5′, J=4.5, 11.8Hz), 3.57 (dd, 1H, H-5′, J=4.3, 11.8 Hz), 2.79 (app quint, 1H, H-2′,J_(app)˜6.5 Hz), 2.39 (ddd, 1H, H-2′, J=2.5, 6.0, 9.5 Hz). ¹³C NMR(DMSO-d₆): δ 160.7, 152.9, 147.9, 147.2, 143.8, 132.9, 130.3, 129.4,128.9, 126.0, 120.8, 120.7, 119.7, 88.6, 84.2, 71.1, 68.6, 61.9, 40.2.

Step 2: Deallylation.

The desilylated product (95.0 mg, 0.218 mmol) obtained in step 1 wasdeallylated as described for 17 using Pd(PPh₃)₄ (12.6 mg, 5 mol %) andPhSO₂Na (35.7 mg, 0.218 mmol) to yield 64.3 mg (75% yield) of 25 as awhite solid. R_(f)(SiO₂/MeOH)=0.54. ¹H NMR (DMSO-d6): δ 9.06 (s, 1H,Ar—H), 8.00 (s, 1H, Ar—H), 7.98 (d, 2H, Ar—H, J=7.6 Hz), 7.46 (t, 2H,Ar—H, J=7.5 Hz), 7.36 (t, 1H, Ar—H, J=7.1 Hz), 6.31 (t, 1H, H-1′, J=6.7Hz), 5.30 (br s, 1H, OH), 4.97 (br s, 1H, OH), 4.42 (br s, 1H, H-3′),3.85 (br s, 1H, H-4′), 3.63-3.60 (m, 1H, H-5′), 3.55-3.50 (m, 1H, H-5′),2.72 (app quint, 1H, H-2′, J_(app)˜6.6 Hz), 2.24 (br dd, 1H, H-2′,J=3.0, 11.3 Hz). ¹³C NMR (DMSO-d6): δ 166.8, 150.8, 149.9, 146.0, 136.7,131.1, 129.3, 128.3, 125.8, 121.5, 120.0, 88.1, 83.6, 71.5, 62.4, 40.1.HRMS calculated for C₁₈H₁₇N₇O₄Na [M+Na]⁺: 418.1234, found: 418.1240.

Example 29 2-[4-(4-Methoxyphenyl)-1,2,3-triazol-1H-yl]-2′-deoxyinosine(26) Step 1: Desilylation.

Using the procedure described for the desilylation of 17, this compoundwas synthesized from 12 (171.0 mg, 0.24 mmol) and Et₃N.3HF (133 μL,0.821 mmol). Chromatography of the crude reaction mixture on a silicagel column using 10% MeOH in EtOAc yielded 104.1 mg (93% yield) of theO⁶-allyl-protected nucleoside as a white, foamy solid. R_(f)(SiO₂/10%MeOH in EtOAc)=0.38. ¹H NMR (DMSO-d₆): δ 9.33 (s, 1H, Ar—H) 8.72 (s, 1H,Ar—H), 7.99 (d, 2H, Ar—H, J=8.6 Hz), 7.07 (d, 2H, Ar—H, J=8.6 Hz), 6.48(t, 1H, H-1′, J=6.7 Hz), 6.26-6.18 (m, 1H, ═CH), 5.56 (d, 1H,═CH_(trans), J=17.4 Hz), 5.42 (d, 1H, OH, J=4.0 Hz), 5.38 (d, 1H,═CH_(cis), J=10.5 Hz), 5.28 (d, 2H, OCH₂, J=5.6 Hz), 4.96 (t, 1H, OH,J=5.4 Hz), 4.49 (br s, 1H, H-3′), 3.92 (br d, 1H, H-4′, J=2.9 Hz), 3.82(s, 3H, OCH₃), 3.68-3.64 (m, 1H, H-5′), 3.60-3.55 (m, 1H, H-5′), 2.80(app quint, 1H, H2′, J_(app)˜7.0 Hz), 2.40 (ddd, 1H, H-2′, J=3.0, 6.5,10.5 Hz).

Step 2: Deallylation.

The desilylated product (100.0 mg, 0.214 mmol) obtained in step 1 wasdeallylated as described for 17 using Pd(PPh₃)₄ (12.4 mg, 5 mol %) andPhSO₂Na (35.1 mg, 0.048 mmol) to yield 78.1 mg (80% yield) of 26 as apale yellow solid. R_(f)(SiO₂/MeOH)=0.46. ^(1H) NMR (DMSO-d₆): δ 8.97(s, 1H, Ar—H), 8.02 (s, 1H, Ar—H), 7.91 (d, 2H, Ar—H, J=8.1 Hz), 7.03(d, 2H, Ar—H, J=8.1 Hz), 6.32 (t, 1H, H-1′, J=6.6 Hz), 5.30 (br s, 1H,OH), 4.99 (br s, 1H, OH), 4.43 (br s, 1H, H-3′), 3.86 (br s, 1H, H-4′),3.80 (s, 3H, OCH₃), 3.63-3.61 (m, 1H, H-5′), 3.54-3.52 (m, 1H, H-5′),2.73 (app quint, 1H, H-2′, J_(app)˜6.6 Hz), 2.25 (br dd, 1H, H-2′,J=5.5, 11.5 Hz). ¹³C NMR (DMSO-d₆): δ 166.9, 159.4, 150.9, 149.9, 145.9,139.6, 127.1, 124.4, 123.7, 119.0, 114.7, 88.1, 83.5, 71.5, 62.4, 55.6,40.1. HRMS calculated for C₁₉H₁₉N₇O₅Na [M+Na]⁺: 448.1340, found:448.1346.

Example 30 2-[4-(Hydroxymethyl)-1,2,3-triazol-1H-yl]-2′-deoxyinosine(27) Step 1: Desilylation.

Using the procedure described for the desilylation of 17, this compoundwas synthesized from 13 (211.0 mg, 0.341 mmol) and Et₃N.3HF (183 μL,1.13 mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 15% MeOH in EtOAc yielded 103.5 mg (78% yield) of theO⁶-allyl-protected nucleoside as a white, foamy solid. R_(f)(SiO₂/10%MeOH in EtOAc)=0.33. ^(1H) NMR (DMSO-d6): δ 8.77 (s, 1H, Ar—H), 8.70 (s,1H, Ar—H), 6.48 (t, 1H, H-J=6.8 Hz), 6.23-6.15 (m, 1H, ═CH), 5.53 (br d,1H, ═CH_(trans), J=17.3 Hz), 5.38 (d, 1H, OH, J=4.2 Hz), 5.35 (br d, 1H,═CH_(cis), J=10.6 Hz), 5.36 (t, 1H, OH, J=5.6 Hz), 5.22 (d, 2H, OCH₂,J=5.9 Hz), 4.92 (t, 1H, OH, J=5.6 Hz), 4.64 (d, 2H, CH₂, J=5.6 Hz), 4.46(m, 1H, H-3′), 3.91 (app q, 1H, H-4′, J_(app)˜3.2 Hz), 3.65-3.61 (m, 1H,H-5′), 3.57-3.52 (m, 1H, H-5′), 2.78 (app sextet, 1H, H-2′, J_(app)˜6.5Hz), 2.40 (ddd, 1H, H-2′, J=3.7, 6.3, 10.0 Hz).

Step 2: Deallylation.

The desilylated product (82.0 mg, 0.210 mmol) obtained in step 1 wasdeallylated as described for 17 using Pd(PPh₃)₄ (12.1 mg, 5 mol %) andPhSO₂Na (34.4 mg, 0.210 mmol) to yield 65.0 mg (88% yield) of 27 as apale yellow solid. R_(f)(SiO₂/MeOH)=0.50. ^(1H) NMR (DMSO-d6): δ 8.44(s, 1H, Ar—H), 7.98 (s, 1H, Ar—H), 6.28 (t, 1H, H-1′, J=6.4 Hz), 5.30(d, 1H, OH, J=3.4 Hz), 5.24 (t, 1H, OH, J=5.7 Hz), 4.96 (t, 1H, OH,J=5.4 Hz), 4.58 (d, 2H, CH₂, J=5.0 Hz), 4.40 (br s, 1H, H-3′), 3.84 (brs, 1H, H-4′), 3.61-3.58 (m, 1H, H-5′), 3.52-3.50 (m, 1H, H-5′), 2.70(app quint, 1H, H-2′, J_(app)˜5.5 Hz), 2.22 (br dd, 1H, H-2′, J=3.0,12.7 Hz). ¹³C NMR (DMSO-d6): δ 166.5, 150.6, 149.9, 147.8, 136.8, 124.3,121.5, 88.1, 83.5, 71.4, 62.4, 55.4, 40.1. HRMS calculated forC₁₃H₁₅N₇O₅Na [M+Na]⁺: 372.1027, found: 372.1029.

Example 312-[4-(N-Phthalimidomethyl)-1,2,3-triazol-1H-yl]-2′-deoxyinosine (28)Step 1: Desilylation.

Using the procedure described for the desilylation of 17, this compoundwas synthesized from 14 (289.0 mg, 0.387 mmol) and Et₃N.3HF (201 μL,1.29 mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 10% MeOH in EtOAc yielded 159.3 mg (79% yield) of theO⁶-allyl-protected nucleoside as a yellow, foamy solid. R_(f)(SiO₂/10%MeOH in EtOAc)=0.56. ¹H NMR (DMSO-d₆): δ 8.91 (s, 1H, Ar—H), 8.70 (s,1H, Ar—H), 7.93 (br d, 2H, Ar—H, J=3.6 Hz), 7.88 (br d, 2H, Ar—H, J=3.6Hz), 6.46 (t, 1H, H-1′, J=6.7 Hz), 6.21-6.13 (m, 1H, ═CH), 5.52 (d, 1H,═CH_(trans), J=16.5 Hz), 5.38 (d, 1H, OH, J=4.0 Hz), 5.34 (d, 1H,═CH_(cis), J=10.6 Hz), 5.20 (d, 2H, OCH₂, J=5.6 Hz), 4.97 (s, 2H, NCH₂),4.92 (t, 1H, OH, J=5.4 Hz), 4.45 (br s, 1H, H-3′), 3.89 (br d, 1H, H-4′,J=2.8 Hz), 3.64-3.60 (m, 1H, H-5′), 3.56-3.52 (m, 1H, H-5′), 2.80 (appquint, 1H, H-2′, J_(app)˜6.5 Hz), 2.36 (ddd, 1H, H-2′, J=3.4, 6.0, 9.6Hz).

Step 2: Deallylation.

The desilylated product (144.0 mg, 0.277 mmol) obtained in step 1 wasdeallylated as described for 17 using Pd(PPh₃)₄ (16.0 mg, 5 mol %) andPhSO₂Na (45.4 mg, 0.277 mmol) to yield 98.9 mg (75% yield) of 28 as apale yellow solid. R_(f)(SiO₂/MeOH)=0.49. ^(1H) NMR (DMSO-d₆): δ 8.54(s, 1H, Ar—H), 7.97 (s, 1H, Ar—H), 7.92 (dd, 2H, Ar—H, J=3.0, 5.4 Hz),7.86 (dd, 2H, Ar—H, J=3.0, 5.4 Hz), 6.26 (t, 1H, H-1′, J=6.2 Hz), 5.32(d, 1H, OH, J=4.0 Hz), 4.94 (t, 1H, OH, J=5.7 Hz), 4.81 (s, 2H, NCH₂),4.38 (br s, 1H, H-3′), 3.85 (app q, 1H, H-4′, J_(app)˜4.5 Hz), 3.60-3.57(m, 1H, H-5′), 3.56-3.48 (m, 1H, H-5′), 2.70 (app quint, 1H, H-2′,J_(app)˜5.5 Hz), 2.38 (ddd, 1H, H-2′, J=2.5, 5.2, 11.0 Hz). ¹³C NMR(DMSO-d₆): δ 167.8, 166.6, 150.6, 149.8, 142.2, 136.7, 134.9, 132.1,124.4, 123.6, 122.1, 88.1, 83.5, 71.4, 62.4, 40.2, 33.3. HRMS calculatedfor C₂₁H₁₈N₈O₆Na [M+Na]⁺: 501.1242, found: 501.1241.

Example 32 2-[4-(Ferrocenyl)-1,2,3-triazol-1H-yl]-2′-deoxyinosine (29)Step 1: Desilylation.

Using the procedure described for the desilylation of 17, this compoundwas synthesized from 15 (394.0 mg, 0.480 mmol) and Et₃N.3HF (257 μL,1.60 mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 10% MeOH in EtOAc yielded 240.8 mg (84% yield) of theO⁶-allyl-protected nucleoside as a brown, foamy solid. R_(f)(SiO₂/10%MeOH in EtOAc)=0.58. ¹H NMR (DMSO-d₆): δ 9.00 (s, 1H, A-H) 8.71 (s, 1H,Ar—H), 6.51 (t, 1H, H-1′, J=6.7 Hz), 6.26-6.18 (m, 1H, ═CH), 5.57 (dd,1H, ═CH_(trans), J=1.5, 17.2 Hz), 5.42 (d, 1H, OH, J=4.0 Hz), 5.34 (brd, 1H, ═CH_(cis), J=11.2 Hz), 5.28 (d, 2H, OCH₂, J=5.6 Hz), 4.96 (t, 1H,OH, J=5.5 Hz), 4.94 (s, 2H, ferrocenyl-H), 4.49 (br s, 1H, H-3′), 4.39(s, 2H, ferrocenyl-H), 4.10 (s, 5H, ferrocenyl-H), 3.92 (br d, 1H, H-4′,J=3.0 Hz), 3.68-3.64 (m, 1H, H-5′), 3.60-3.56 (m, 1H, H-5′), 2.78 (appquint, 1H, H2′, J_(app)˜6.5 Hz), 2.40 (ddd, 1H, H-2′, J=3.5, 6.5, 9.5Hz).

Step 2: Deallylation.

The desilylated product (189.0 mg, 0.319 mmol) obtained in step 1 wasdeallylated as described for 17 using Pd(PPh₃)₄ (18.4 mg, 5 mol %) andPhSO₂Na (52.3 mg, 0.319 mmol) to yield 135.1 mg (84% yield) of 29 as abrownish red solid. R_(f)(SiO₂/MeOH)=0.53. ^(1H) NMR (DMSO-d₆): δ 8.65(s, 1H, Ar—H), 7.98 (s, 1H, Ar—H), 6.51 (t, 1H, H-1′, J=6.2 Hz), 5.32(d, 1H, OH, J=3.9 Hz), 4.98 (t, 1H, OH, J=5.7 Hz), 4.86 (s, 2H,ferrocenyl-H), 4.42 (br s, 1H, H-3′), 4.34 (s, 2H, ferrocenyl-H), 4.07(s, 5H, ferrocenyl-H), 3.86 (br d, 1H, H-4′, J=2.3 Hz), 3.64-3.60 (m,1H, H-5′), 3.56-3.51 (m, 1H, H-5′), 2.71 (app quint, 1H, H-2′,J_(app)˜6.6 Hz), 2.24 (ddd, 1H, H2′, J=2.0, 6.0. 10.9 Hz). ¹³C NMR(DMSO-d₆): δ 166.6, 150.7, 149.9, 145.2, 136.5, 131.9, 129.1, 118.9,88.1, 83.5, 76.2, 71.5, 69.6, 68.7, 66.8, 62.4, 40.2. HRMS calculatedfor C₂₂H₂₁FeN₇O₄Na [M+Na]⁺: 526.0897, found: 526.0890.

Example 33 2-(4-n-Butyl-1,2,3-triazol-1H-yl)-2′-deoxyinosine (30) Step1: Desilylation.

Using the procedure described for the desilylation of 17, this compoundwas synthesized from 16 (275.1 mg, 0.427 mmol) and Et₃N.3HF (231 μL,1.42 mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 8% MeOH in EtOAc yielded 152.3 mg (86% yield) of theO⁶-allyl-protected nucleoside as a brown, foamy solid. R_(f)(SiO₂/10%MeOH in EtOAc)=0.50. ¹H NMR (DMSO-d₆): δ 8.70 (s, 2H, Ar—H), 6.48 (t,1H, H-1′, J=6.6 Hz), 6.24-6.16 (m, 1H, ═CH), 5.54 (d, 1H, ═CH_(trans),J=17.2 Hz), 5.39 (br s, 1H, OH), 5.36 (d, 1H, ═CH_(cis), J=10.6 Hz),5.22 (d, 2H, OCH₂, J=5.4 Hz), 4.93 (br s, 1H, OH), 4.48 (br s, 1H,H-3′), 3.91 (br d, 1H, H-4′, J=2.7 Hz), 3.65 (br d, 1H, H-5′, J=10.5Hz), 3.57 (br d, 1H, H-5′, J=10.5 Hz), 2.80-2.73 (m, 3H, butyl-CH₂, andH-2′) 2.38 (br dd, 1H, H-2′, J=3.4, 7.5 Hz), 1.69 (quint, 2H, butyl-CH₂,J=7.5 Hz), 1.39 (sextet, 2H, butyl-CH₂, J=7.5 Hz), 0.94 (t, 3H,butyl-CHs, J=7.3 Hz).

Step 2: Dealtylation.

The desilylated product (144.0 mg, 0.346 mmol) obtained in step 1 wasdeallylated as described for 17 using Pd(PPh₃)₄ (20.0 mg, 5 mol %) andPhSO₂Na (56.7 mg, 0.346 mmol) to yield 89.3 mg (69% yield) of 30 aswhite solid. R_(f)(SiO₂/MeOH)=0.55. ¹H NMR (DMSO-d₆): δ 8.35 (s, 1H,Ar—H), 8.00 (s, 1H, Ar—H), 6.28 (t, 1H, H-1′, J=6.3 Hz), 5.32 (br s, 1H,OH), 4.98 (br s, 1H, OH), 4.41 (br s, 1H, H-3′), 3.85 (br s, 1H, H-4′),3.61-3.59 (m, 1H, H-5′), 3.52-3.50 (m, 1H, H-5′), 2.73-2.65 (m, 3H,butyl-CH₂, and H-2′), 2.38 (ddd, 1H, H-2′, J=3.5, 8.5, 11.0 Hz), 1.63(quint, 2H, butyl-CH₂, J=7.4 Hz), 1.35 (sextet, 2H, butyl-CH₂, J=7.4Hz), 0.91 (t, 3H, butyl-CHs, J=7.3 Hz). ¹³C NMR (DMSO-d₆): δ 166.9,150.8, 149.9, 146.8, 136.7, 124.2, 120.6, 88.1, 83.5, 71.5, 62.4, 40.1,31.4, 25.0, 22.1, 14.1. HRMS calculated for C₁₆H₂₁N₇O₄Na [M+Na]⁺:398.1547, found: 398.1553.

Example 34O⁶-(1-Benzotriazol-1H-yl)-2-(4-phenyl-1,2,3-triazol-1H-yl)-2′,3′,5′-tri-O-(tert-butyldimethylsilyl)inosine(31) Step 1: Dealtylation.

Following the procedure described for the preparation of 17, compound 3(170 mg, 0.214 mmol) was deallylated using Pd(PPh₃)₄ (12.3 mg, 5 mol %)and PhSO₂Na (35.1 mg, 0.214 mmol). Chromatographic purification of thecrude material on a silica gel column using 10% MeOH in EtOAc afforded146.3 mg (91% yield) of the deallylated compound as a clear gum.R_(f)(SiO₂/10% MeOH in EtOAc)=0.46. ¹H NMR (DMSO-d₆): δ 8.96 (s, 1H,Ar—H), 8.05 (s, 1H, Ar—H), 7.95 (d, 2H, Ar—H, J=7.6 Hz), 7.47 (t, 2H,Ar—H, J=7.2 Hz), 7.36 (t, 1H, Ar—H, J=7.2 Hz), 5.85 (d, 1H, H-1′, J=6.4Hz), 5.12 (t, 1H, H-2′, J=5.0 Hz), 4.30 (br s, 1H, H-3′), 4.08 (dd, 1H,H-5′, J=6.9, 10.8 Hz), 3.97 (br s, 1H, H-4′), 3.72 (dd, 1H, H-5′, J=3.5,10.8 Hz), 0.92, 0.86, and 0.72 (3s, 27H, t-Bu), 0.14, 0.12, 0.07, 0.05,−0.10, and −0.31 (6s, 18H, SiCH₃).

Step 2: Introduction of the O⁶-Benzotriazolyl Group.

In a clean, dry round-bottomed flask equipped with a stifling bar wereplaced the2-[(4-phenyl)-1,2,3-triazol-1H-yl]-2′,3′-5′-tri-O-(tert-butyldimethylsilyl)inosinederivative 3 (160.0 mg, 0.212 mmol), BOP (187.7 mg, 0.424 mmol), andi-Pr2NEt (45 μL, 0.318 mmol) in dry THF (4.0 mL). The reaction mixturewas flushed with nitrogen gas, and stirred at room temperature for 24 h,at which time TLC indicated complete reaction. The mixture was dilutedwith EtOAc and washed with water containing a small amount of NaCl, theaqueous layer was separated and reextracted with EtOAc. The combinedorganic layer was dried over Na₂SO₄ and evaporated to dryness.Chromatographic purification of the crude material on a silica gelcolumn using 20% EtOAc in hexanes provided 101.4 mg (55% yield) of 31 asa white foam. R_(f)(SiO₂/20% EtOAc in hexanes)=0.57. ¹H NMR (CDCl₃): δ8.75 (s, 1H, Ar—H), 8.21 (d, 1H, Ar—H, J=8.4 Hz), 7.87 (s, 1H, Ar—H),7.74 (d, 2H, Ar—H, J=7.3 Hz), 7.59-7.49 (m, 3H, Ar—H), 7.40 (t, 2H,Ar—H, J=7.4 Hz), 7.33 (t, 1H, Ar—H, J=7.4 Hz), 6.21 (d, 1H, H-1′, J=3.7Hz), 4.61 (t, 1H, H-2′, J=3.9 Hz), 4.37 (t, 1H, H-3′, J=4.6 Hz), 4.22(app q, 1H, H-4′, J_(app)˜3.6 Hz), 4.14 (dd, 1H, H-5′, J=3.6, 11.6 Hz),3.85 (dd, 1H, H-5′, J=2.5, 11.6 Hz), 0.98, 0.93, and 0.85 (3s, 27H,t-Bu), 0.19, 0.17, 0.12, 0.09, 0.06, and 0.02 (6s, 18H, SiCH₃). ¹³C NMR(CDCl₃): δ159.7, 155.1, 147.9, 147.8, 145.4, 143.6, 129.8, 129.4, 129.2,129.0, 128.8, 126.1, 125.3, 120.9, 119.4, 118.5, 108.8, 89.7, 85.4,76.6, 71.2, 62.1, 26.3, 26.0, 25.9, 18.8, 18.3, 18.1, −4.1, −4.6, −5.1,−5.2. FIRMS calculated for C₄₂H₆₃N₁₀O₅Si₃ [M+H]⁺: 871.4285, found:871.4298.

Example 356-(Morpholin-4-yl)-2-(4-phenyl-1,2,3-triazol-1H-yl)-9-[2′,3′,5′-tri-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]purine(32)

In a clean, dry reaction vial equipped with a stirring bar was placed 31(50.0 mg, 0.057 mmol) in dry DME (2 mL). Morpholine (20.0 μL, 0.229mmol) was added, the reaction mixture was flushed with nitrogen gas, andallowed to stir at room temperature for 1 h. The reaction mixture wasevaporated, the residue was dissolved in EtOAc and washed with watercontaining a small amount of NaCl. The aqueous layer was separated andreextracted with EtOAc. The combined organic layer was dried over Na₂SO₄and evaporated to dryness. Chromatographic purification of the crudematerial on a silica gel column using 20% EtOAc in hexanes afforded 36.1mg (77% yield) of 32 as a white foam. R_(f)(SiO₂/30% EtOAc inhexanes)=0.70. ¹H NMR (CDCl₃): δ 8.69 (s, 1H, Ar—H), 8.20 (s, 1H, Ar—H),7.95 (d, 2H, Ar—H, J=7.2 Hz), 7.46 (t, 2H, Ar—H, J=7.5 Hz), 7.36 (t, 1H,Ar—H, J=7.5 Hz), 6.11 (d, 1H, H-1′, J=4.5 Hz), 4.60 (t, 1H, H-2′, J=4.5Hz), 4.48-4.35 (br m, 4H, 2CH₂), 4.34 (t, 1H, H-3′, J=4.3 Hz), 4.15 (appq, 1H, H-4′, J_(app)˜3.6 Hz), 4.08 (dd, 1H, H-5′, J=3.7, 11.4 Hz), 3.88(t, 4H, 2CH₂, J=4.8 Hz), 3.82 (dd, 1H, H-5′, J=2.8, 11.4 Hz), 0.96,0.94, and 0.88 (3s, 27H, t-Bu), 0.16, 0.14, 0.12, 0.10, 0.01, and −0.06(6s, 18H, SiCH₃). ¹³C NMR (CDCl₃): δ 153.8, 151.3, 149.0, 147.2, 138.3,130.4, 128.8, 128.2, 125.9, 119.5, 118.4, 88.3, 85.0, 75.9, 71.5, 66.9,62.3, 45.8 (br s), 26.1, 25.8, 25.6, 18.5, 18.0, 17.8, −4.3, −4.7, −5.3.HRMS calculated for C₄₀H₆₇N₈O₅Si₃ [M+H]⁺: 823.4537, found: 823.4550.

Example 366-(N-Benzyl)-2-(4-phenyl-1,2,3-triazol-1H-yl)-2′,3′,5′-tri-O-(tert-butyldimethylsilyl)adenosine(33)

As described for the synthesis of 32, this compound was prepared by areaction between 31 (50.0 mg, 0.057 mmol) and benzylamine (25.0 μL,0.228 mmol) in dry DME (2.0 mL) at room temperature over 10 h. Workup asdescribed for 32 and chromatographic purification of the crude materialon a silica gel column using 20% EtOAc in hexanes afforded 43.1 mg (90%yield) of 33 as a white foam. R_(f)(30% EtOAc in hexanes)=0.55. ¹H NMR(CDCl₃): δ 8.68 (s, 1H, Ar—H), 8.41 (br s, 1H, Ar—H), 7.95 (d, 2H, Ar—H,J=7.8 Hz), 7.48-7.45 (m, 4H, Ar—H Hz), 7.38-7.34 (m, 3H, Ar—H), 7.28(app t, 1H, Ar—H, J=7.3 Hz), 6.90 (br s, 1H, NH), 6.10 (d, 1H, H-1′,J=3.8 Hz), 4.93 (br s, 2H, CH₂), 4.58 (t, 1H, H-2′, J=3.9 Hz), 4.34 (t,1H, H-3′, J=4.6 Hz), 4.17 (br s, 1H, H-4′), 4.12 (br d, 1H, H-5′, J=11.0Hz), 3.83 (dd, 1H, H-5′, J=2.0, 11.0 Hz), 0.97, 0.92, and 0.86 (3s, 27H,t-Bu), 0.17, 0.15, 0.11, 0.09, 0.05, and 0.02 (6s, 18H, SiCH₃). ¹³C NMR(CDCl₃): δ 154.3, 150.3, 148.8, 147.4, 138.5, 137.7, 130.4, 128.9,128.8, 128.4, 128.1, 127.8, 126.0, 118.7, 89.3, 84.3, 76.2, 70.6, 61.8,60.4, 45.2, 26.2, 25.9, 25.8, 18.6, 18.1, 18.0, −4.1, −4.4, −4.7, −5.1,−5.3. HRMS calculated for C₄₃H₆₇N₈O₄Si₃ [M+H]⁺: 843.4588, found:843.4596.

Example 376-(Morpholin-4-yl)-2-(4-phenyl-1,2,3-triazol-1H-yl)-9-(β-D-ribofuranosyl)purine(34)

Using the procedure described for the desilylation of 17, this compoundwas synthesized from 32 (30.0 mg, 0.036 mmol) and Et₃N.3HF (29.0 μL,0.18 mmol). Chromatography of the crude reaction mixture on a silica gelcolumn using 10% MeOH in EtOAc yielded 13.9 mg (80% yield) of 34 as awhite, foamy solid. R_(f)(SiO_(2/30)% MeOH in EtOAc)=0.57. ¹H NMR(DMSO-d₆): δ 9.34 (s, 1H, Ar—H), 8.55 (s, 1H, Ar—H), 8.05 (d, 2H, Ar—H,J=7.8 Hz), 7.50 (t, 2H, Ar—H, J=7.5 Hz), 7.39 (t, 1H, Ar—H, J=7.5 Hz),6.03 (d, 1H, H-1′, J=5.8 Hz), 5.53 (d, 1H, OH, J=6.0 Hz), 5.27 (d, 1H,OH, J=4.9 Hz), 5.01 (t, 1H, OH, J=5.6 Hz), 4.64 (app quint, 1H, H-2′,J_(app)˜5.8 Hz), 4.48-4.35 (br m, 4H, 2CH₂), 4.22 (app q, 1H, H-3′,J_(app)˜4.8 Hz), 3.98 (app q, 1H, H-4′, J=3.8 Hz), 3.80 (t, 4H, 2CH₂,J=4.8 Hz), 3.79-3.70 (m, 1H, H-5′), 3.62-3.58 (m, 1H, H-5′). ¹³C NMR(DMSO-d₆): δ 153.7, 151.8, 148.8, 146.9, 140.2, 130.5, 129.3, 128.3,126.0, 120.5, 119.2, 87.7, 86.2, 74.2, 70.8, 66.6, 61.8, 46.0 (br s).HRMS calculated for C₂₂H₂₄N₈O₅Na [M+Na]⁺: 503.1762, found: 503.1765.

Example 38 6-(N-Benzyl)-2-[4-(phenyl)-1,2,3-triazol-1H-yl]adenosine (35)

Using the procedure described for the desilylation of 17, this compoundwas synthesized from 33 (35.0 mg, 0.041 mmol) and Et₃N.3HF (34.0 μL,0.207 mmol). Chromatography of the crude reaction mixture on a silicagel column using 10% MeOH in EtOAc yielded 16.8 mg (82% yield) of 35 asa white, foamy solid. R_(f) (SiO₂/30% MeOH in EtOAc)=0.44. ¹H NMR(DMSO-d₆): δ 9.22 (s, 1H, Ar—H), 9.04 (br s, 1H, NH), 8.51 (s, 1H,Ar—H), 8.02 (d, 2H, Ar—H, J=7.6 Hz), 7.50 (m, 4H, Ar—H), 7.39 (t, 1H,Ar—H, J=7.3 Hz), 7.33 (t, 2H, Ar—H, J=7.5 Hz), 7.23 (t, 1H, Ar—H, J=7.3Hz), 6.00 (d, 1H, H-1′, J=6.0 Hz), 5.51 (d, 1H, OH, J=5.6 Hz), 5.25 (d,1H, OH, J=3.9 Hz), 5.00 (t, 1H, OH, J=5.8 Hz), 4.81-4.90 (m, 2H, CH₂),4.69-4.62 (m, 1H, H-2′), 4.28-4.24 (m, 1H, H-3′), 4.17 (m, 1H, H-4′),3.72-3.70 (m, 1H, H-5′), 3.62-3.58 (m, 1H, H-5′). ¹³C NMR (DMSO-d₆): δ155.1, 151.3, 149.8, 149.3, 146.8, 141.1, 140.0, 130.5, 129.3, 128.7,128.1, 127.3, 126.0, 120.3, 119.4, 87.6, 86.2, 74.1, 70.9, 61.9, 43.8.HRMS calculated for C₂₅H₂₄N₈O₄Na [M+Na]⁺: 523.1813, found: 523.1822.

Example 392-Azido-O⁶-(benzotriazol-1H-yl)-2′,3′,5′-tri-O-(tert-butyldimethylsilypinosine(38)

A solution of 37 (50.0 mg, 0.067 mmol) in CH₂Cl₂ (3 mL) was cooled to78° C. To this stirred solution TMS-N3 (0.088 mL, 0.67 mmol) was addedfollowed by dropwise addition of t-BuONO (0.08 mL, 0.67 mmol). Thereaction mixture was allowed to warm to rt and stirred for 9 h. To thereaction mixture were added 1:1 H₂O/MeOH (1 mL) and the stifling wascontinued for 1 h. The mixture was then extracted with CH₂Cl₂. Afterlayer separation, the organic layer was removed, washed with water,dried over Na₂SO₄ and evaporated to dryness. The crude product waspurified on silica gel column using 10% EtOAc/hexanes to afford 25.5 mg(49% yield) of 38 as white, foamy solid. R_(f) (SiO₂/30% EtOAc inhexanes)=0.66. IR (neat): 2955, 2930, 2857, 2128, 1618, 1570 cm⁻¹. Thefollowing ¹H and ¹³C NMR data list all discernible signals of the isomermixture. ¹H NMR (500 MHz, CDCl₃): δ 8.63, 8.58, and 8.55 (3s, 1H, Ar—H),8.13 (m, 1H, Ar—H), 7.57-7.43 (m, 3H, Ar—H), 6.16 and 6.05 (2d, 1H,H-1′, J=4.9, 3.9 Hz, respectively), 4.58, 4.54, and 4.47 (3t, 1H, H-2′,J=4.4, 4.2, 4.2 Hz, respectively), 4.35-4.31 (m, 1H, H-3′), 4.19-4.15(m, 1H, H-4′), 4.08-4.02 (m, 1H, H-5′), 3.83-3.79 (m, 1H, H-5′), 0.972,0.969, 0.96, 0.93, 0.925, 0.85, 0.84, and 0.81 (8s, 27H, t-Bu), 0.17,0.16, 0.15, 0.10, 0.09, 0.02, 0.01, −0.008, −0.12, and −0.17 (10s, 18H,SiCH₃). ¹³C NMR (125 MHz, CDCl₃): δ 159.81, 159.22, 155.97, 155.60,155.10, 154.06, 152.81, 151.63, 144.62, 144.09, 143.72, 143.64, 143.57,129.21, 129.12, 129.03, 128.94, 128.91, 125.14, 125.06, 125.03, 120.84,120.10, 119.22, 117.19, 108.86, 108.77, 108.72, 89.61, 89.06, 88.99,85.70, 85.56, 85.39, 76.66, 76.61, 76.46, 71.76, 71.47, 71.42, 62.45,62.28, 62.19, 26.33, 26.31, 26.02, 25.86, 18.78, 18.75, 18.27, 18.09,18.07, −4.09, −4.12, −4.15, −4.45, −4.49, −4.53, −4.57, −4.59, −4.72,−5.11, −5.19, −5.23. HRMS calculated for C₃₄H₅₇N₁₀O₅Si₃ [M+H]⁺ 769.3816,found 769.3839.

Example 40 Biological Assay Protocol

The cytostatic effects of the test compounds on murine leukemia cells(L1210), human T-lymphocyte cells (CEM) and human cervix carcinoma cells(HeLa) were evaluated as follows: an appropriate number of cellssuspended in growth medium were allowed to proliferate in 200-μL-wellsof 96-well-microtiter plates in the presence of variable amounts of testcompounds at 37° C. in a humidified CO₂-controlled atmosphere. After 48h (L1210), 72 h (CEM) or 96 h (HeLa), the number of cells was counted ina Coulter counter. The IC₅₀ value is defined as the concentrationrequired to inhibit cell proliferation by 50%.

The antiviral assays (except anti-human immunodeficiency virus (HIV)assays) were based on inhibition of virus-induced cytopathicity in HEL[herpes simplex virus type 1 (HSV-1), HSV-2 (G), vaccinia virus, andvesicular stomatitis virus, cytomegalovirus, and varicella-zostervirus], Vero (parainfluenza-3, reovirus-1, Coxsackie B4, and Punta Torovirus), HeLa (vesicular stomatitis virus, Coxsackie virus B4, andrespiratory syncytial virus), MDCK (influenza A (H1N1; H3N2) and Bvirus) and CrFK (feline corona virus (FIPV) and feline herpes virus)cell cultures. Confluent cell cultures in microtiter 96-well plates wereinoculated with 100 cell culture inhibitory dose-50 (CCID₅₀) of virus (1CCID₅₀ being the virus dose to infect 50% of the cell cultures) in thepresence of varying concentrations (100, 20, 4, 0.8 μg/mL) of the testcompounds. Viral cytopathicity was recorded as soon as it reachedcompletion in the control virus-infected cell cultures that were nottreated with the test compounds.

The methodology of the anti-HIV assays was as follows: human CEM (˜3×10⁵cells/mL) cells were infected with 100 CCID50 of HIV(III_(B)) orHIV-2(ROD)/mL and seeded in 200 μL wells of a microtiter platecontaining appropriate dilutions of the test compounds. After 4 days ofincubation at 37° C., HIV-induced CEM giant cell formation was examinedmicroscopically. The 50% effective concentration (EC₅₀) was defined asthe compound concentration required to inhibit syncytia formation by50%. The 50% cytostatic concentration (CC₅₀) was defined as the compoundconcentration required to inhibit CEM cell proliferation by 50% incomparison to mock-infected cell cultures.

Determination of GI₅₀s using ovarian cancer and colon carcinoma celllines were essentially as described. See Lakshman, M. K.; Singh, M. K.;Parrish, D.; Balachandran, R.; Day, B. W. J. Org. Chem. 2010, 75,2461-2473; Cui, Y.; Balachandran, R.; Day, B. W.; Floreancig, P. E. J.Org. Chem. 2012, 77, 2225-2235; Wan, S.; Wu, F.; Rech, J. C.; Green, M.E.; Balachandran, R.; Home, S. W.; Day, B. W.; Floreancig, P. E. J. Am.Chem. Soc. 2011, 133, 16668-16679; and Zhu, W.; Jimenez, M.; Jung, W.H.; Camarco, D. P.; Balachandran, R.; Vogt, A.; Day, B. W.; Curran, D.P. J. Am. Chem. Soc. 2010, 132, 9175-9187.

A 10 mM stock solution of paclitaxel (PTX), obtained from the DrugSynthesis Branch of the National Cancer Institute, was prepared in DMSO.Control samples contained 1% (v/v) DMSO vehicle, a level equivalent tothat in the drug-treated cultures. Ovarian cancer cells were cultured inRPMI 1640 medium without phenol red containing 10% fetal bovine serum at37° C. in a humidified 5% carbon dioxide incubator. 1A9/PTX10 and1A9/PTX22 cells were maintained in the presence of 15 ng/mL PTX and 5μg/mL verapamil. This medium was replaced with regular medium two tothree days before plating the cells in 96 well plates. HCT116 andp53KO^(−/−) cell lines were maintained in McCoy medium with 10% fetalbovine serum.

Cells were plated in 96-well tissue culture plates for 48 h and thecompounds (prepared in 100% DMSO as a stock solution) were added inquadruplicate. At least five different concentrations were tested foreach compound. In each experiment, one plate consisted entirely of cellsand medium used for time zero cell number determination, at the time/dayof addition of compounds. After four days, 20 μL of Promega Cell Titerreagent was added into each well and plates were incubated in the tissueculture incubator. Approximately 2 h later, the plates were read using aplate reader at 490 nm minus 630 nm absorbance wavelengths. The data wasthen analyzed using an Excel Spreadsheet grid. Resulting average valuesranging from <50 or >50 cell culture expansion for two or moreconcentrations were used to calculate the GI₅₀.

1. A compound having Formula I,

wherein: R¹ represents an alkyl, an aryl, —SiR⁴, —SnR⁵, —B(R⁴)₂,—B(OH)₂, an amide, an imide, or an organometallic; R² and R³independently represent N, CH, or CR⁶; R⁴ independently represents —R⁵or —OR⁵; R⁵, R⁷ and R⁸, independently of each other and independently ateach position, represent alkyl, cycloalkyl, or aryl; R⁷ and R⁸independently, may be combined to represent a heterocyclic alkyl or aheterocyclic aryl; R⁶ independently represents an alkyl or an aryl; Yrepresents H, an alkyl, an aryl, or a saccharide moiety; alkyl groupsare branched or unbranched, saturated or unsaturated, and have 1-18carbon atoms in their longest chain; cycloalkyl groups are carbocyclicor heterocyclic, fused or unfused, non-aromatic ring systems having atotal of 5-16 ring members including substituent rings; aryl groups arecarbocyclic or heterocyclic; carbocyclic aryl groups are fused orunfused ring systems having a total of 6-16 ring members includingsubstituent rings; heterocyclic aryl groups are fused or unfused ringsystems having a total of 5-16 ring members including substituent rings;halo substituents are fluoro, chloro, bromo, or iodo; each alkyl,cycloalkyl, and aryl, independently, may be unsubstituted or substitutedwith one or more substituent at any position; alkyl substituents arehalo, hydroxyl, —OR⁵, —SR⁵, —S(O)R⁴, —S(O)₂R⁴, —NH₂, —NHR⁵, —NR⁷R⁸,cycloalkyl, or aryl; cycloalkyl substituents are halo, hydroxyl, —OR⁵,—SR⁵, —NH₂, —NHR⁵, —NR⁷R⁸, alkyl, cycloalkyl, or aryl; aryl substituentsare halo, hydroxyl, —OR⁵, —SR⁵, —NH₂, —NHR⁵, —NR⁷R⁸, —CN, alkyl,cycloalkyl, aryl, nitro, or carboxyl; and heterocyclic alkyl andheterocyclic aryl have at least one heteroatom selected from the groupconsisting of oxygen, nitrogen and sulfur.
 2. A compound according toclaim 1, wherein Y represents a saccharide moiety, and the saccharidemoiety has the following structure:

wherein: Y¹ represents C, N, or O; R²⁰ and R²¹ independently representH, —OR²³, —NR⁷R⁸, R⁶, or halo; R²² represents H, OH, —CH₂OR⁶, —CH₂OR²³,—NR⁷R⁸, —CH₂NR⁷R⁸, R⁶; and R²³ represents H or a protecting group.
 3. Acompound according to claim 2, wherein Y¹ represents
 0. 4. A compoundaccording to claim 2, wherein R²² represents —CH₂O(alkyl) or —CH₂OR²³.5. A compound according to claim 1, wherein the saccharide moiety isselected from the group consisting of 1-ribosyl and 2′-deoxy-1-ribosyl.6. A compound according to claim 1, wherein R¹ is an imide and the imideis represented by:

wherein: R²⁴ and R²⁵ are independently an alkyl or an aryl; and R²⁴ andR²⁵ independently, may be combined to represent a succinimidyl groupthat may be fused or unfused, and substituted or unsubstituted.
 7. Acompound according to claim 6, wherein R¹ is phthalimidyl.
 8. A compoundaccording to claim 1, wherein R¹ is an amide and the amide isrepresented by:

wherein: R²⁶ and R²⁷ are independently an alkyl or an aryl.
 9. Acompound according to claim 1, wherein R¹ is an organometallic and theorganometallic has a complex of Fe, Mo, Ru, or Pt.
 10. A compoundaccording to claim 9, wherein R¹ is ferrocenyl.
 11. A compound accordingto claim 1, wherein Y represents a saccharide moiety selected from thegroup consisting of 1-ribosyl and 2′-deoxy-1-ribosyl; R² is N; R³ is CH;and R¹ represents:


12. A compound having Formula II,

wherein: R¹ represents an alkyl, an aryl, —SiR⁴, —SnR⁵, —B(R⁴)₂,—B(OH)₂, an amide, an imide, or an organometallic; R² and R³independently represent N, CH, or CR⁶; X represents —OR⁹, —SR⁹, or—NR⁹R¹⁰; Y represents H, an alkyl, an aryl, or a saccharide moiety; R⁴independently represents —R⁵ or —OR⁵; R⁵, R⁷ and R⁸, independently ofeach other and independently at each position, represent alkyl,cycloalkyl, or aryl; and R⁶ independently represents an alkyl or anaryl; R⁹ and R¹⁰ independently represent H, an alkyl, or an aryl; R⁷ andR⁸, R⁹ and R¹⁰ independently, may be combined to represent aheterocyclic alkyl or a heterocyclic aryl; alkyl groups are branched orunbranched, saturated or unsaturated, and have 1-18 carbon atoms intheir longest chain; cycloalkyl groups are carbocyclic or heterocyclic,fused or unfused, non-aromatic ring systems having a total of 5-16 ringmembers including substituent rings; aryl groups are carbocyclic orheterocyclic; carbocyclic aryl groups are fused or unfused ring systemshaving a total of 6-16 ring members including substituent rings;heterocyclic aryl groups are fused or unfused ring systems having atotal of 5-16 ring members including substituent rings; halosubstituents are fluoro, chloro, bromo, or iodo; each alkyl, cycloalkyl,and aryl, independently, may be unsubstituted or substituted with one ormore substituent at any position; alkyl substituents are halo, hydroxyl,—OR⁵, —SR⁵, —S(O)R⁴, —S(O)₂R⁴, —NH₂, —NHR⁵, —NR⁷R⁸, cycloalkyl, or aryl;cycloalkyl substituents are halo, hydroxyl, —OR⁵, —SR⁵, —NH₂, —NHR⁵,—NR⁷R⁸, alkyl, cycloalkyl, or aryl; aryl substituents are halo,hydroxyl, —OR⁵, —SR⁵, —NH₂, —NHR⁵, —NR⁷R⁸, —CN, alkyl, cycloalkyl, aryl,nitro, or carboxyl; and heterocyclic alkyl and heterocyclic aryl have atleast one heteroatom selected from the group consisting of oxygen,nitrogen and sulfur.
 13. A compound according to claim 12, wherein X is—NR⁹R¹⁰ and R¹ represents —SiR⁴, —SnR⁵, —B(R⁴)₂, —B(OH)₂, an imide, oran organometallic.
 14. A compound according to claim 12, wherein X is—NR⁹R¹⁰ and R⁹ and R¹⁰ independently represent an alkyl or an aryl. 15.A compound according to claim 12, wherein R² is N and R³ is CH.
 16. Acompound according to claim 12, wherein R¹ is phenyl.
 17. A compoundaccording to claim 12, wherein R⁹ and R¹⁰ independently represent H orCH₂Ph; or R⁹ and R¹⁰ are combined to represent CH₂CH₂OCH₂CH₂.
 18. Acompound according to claim 12, wherein R¹ is an imide and the imide isrepresented by:

wherein: R²⁴ and R²⁵ are independently an alkyl or an aryl; and R²⁴ andR²⁵ independently, may be combined to represent a succinimidyl groupthat may be fused or unfused, and substituted or unsubstituted.
 19. Acompound according to claim 18, wherein R¹ is phthalimidyl.
 20. Acompound according to claim 12, wherein R¹ is an amide and the amide isrepresented by:

wherein: R²⁶ and R²⁷ are independently an alkyl or an aryl.
 21. Acompound according to claim 12, wherein R¹ is an organometallic and theorganometallic has a complex of Fe, Mo, Ru, or Pt.
 22. A compoundaccording to claim 21, wherein R¹ is ferrocenyl.
 23. A compoundaccording to claim 12, wherein Y represents a saccharide moiety, and thesaccharide moiety has the following structure:

wherein: Y¹ represents C, N, or O; R²⁰ and R²¹ independently representH, —OR²³, —NR⁷R⁸, R⁶, or halo; R²² represents H, OH, —CH₂OR⁶, —CH₂OR²³,—NR⁷R⁸, —CH₂NR⁷R⁸, R⁶; and R²³ represents H or a protecting group.
 24. Acompound according to claim 23, wherein Y¹ represents O.
 25. A compoundaccording to claim 23, wherein R²² represents —CH₂O(alkyl) or —CH₂OR²³.26. A compound according to claim 12, wherein the saccharide moiety isselected from the group consisting of 1-ribosyl and 2′-deoxy-1-ribosyl.27. A compound having Formula III,

wherein: R⁹, R¹⁰, R¹²R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ independently representN or CR¹¹; R¹¹ independently represents —R¹⁸, —OR¹⁹, —SR¹⁹, —N(R¹⁸)₂,R¹⁸C(O)—, nitro, or halo; R¹⁸ independently represents H, an alkylgroup, or an aryl; R¹⁹ independently represents R¹⁸ or a protectinggroup; Y represents R¹⁸ or a saccharide moiety; alkyl groups arebranched or unbranched, saturated or unsaturated, and have 1-18 carbonatoms in their longest chain; cycloalkyl groups are carbocyclic orheterocyclic, fused or unfused, non-aromatic ring systems having a totalof 5-16 ring members including substituent rings; aryl groups arecarbocyclic or heterocyclic; carbocyclic aryl groups are fused orunfused ring systems having a total of 6-16 ring members includingsubstituent rings; heterocyclic aryl groups are fused or unfused ringsystems having a total of 5-16 ring members including substituent rings;halo substituents are fluoro, chloro, bromo, or iodo; each alkyl,cycloalkyl, and aryl, independently, may be unsubstituted or substitutedwith one or more substituent at any position; alkyl substituents arehalo, hydroxyl, —OR⁵, —SR⁵, —S(O)R⁴, —S(O)₂R⁴, —NH₂, —NHR⁵, —NR⁷R⁸,cycloalkyl, or aryl; cycloalkyl substituents are halo, hydroxyl, —OR⁵,—SR⁵, —NH₂, —NHR⁵, —NR⁷R⁸, alkyl, cycloalkyl, or aryl; aryl substituentsare halo, hydroxyl, —OR⁵, —SR⁵, —NH₂, —NHR⁵, —NR⁷R⁸, —CN, alkyl,cycloalkyl, aryl, nitro, or carboxyl; and heterocyclic alkyl andheterocyclic aryl have at least one heteroatom selected from the groupconsisting of oxygen, nitrogen and sulfur. R⁴ independently represents—R⁵ or —OR⁵; R⁵, R⁷ and R⁸, independently of each other andindependently at each position, represent alkyl, cycloalkyl, or aryl;and R⁷ and R⁸ independently, may be combined to represent a heterocyclicalkyl or a heterocyclic aryl.
 28. A compound according to claim 27,wherein Y represents a saccharide moiety, and the saccharide moiety hasthe following structure:

wherein: Y¹ represents C, N, or O; R²⁰ and R²¹ independently representH, —OR²³, —NR⁷R⁸, R⁶, or halo; R²² represents H, OH, —CH₂OR⁶, —CH₂OR²³,—NR⁷R⁸, —CH₂NR⁷R⁸, R⁶; R²³ represents H or a protecting group; and R⁶represents an alkyl or an aryl.
 29. A compound according to claim 28,wherein Y¹ represents O.
 30. A compound according to claim 28, whereinR²² represents —CH₂O(alkyl) or —CH₂OR²³.
 31. A compound according toclaim 27, wherein the saccharide moiety is selected from the groupconsisting of 1-ribosyl and 2′-deoxy-1-ribosyl.
 32. A compound accordingto claim 27, wherein no more than one of R¹⁴, R¹⁵, R¹⁶, and R¹⁷represent N.
 33. A compound according to claim 27, wherein R⁹, R¹⁴, R¹⁵,R¹⁶, and R¹⁷ are CH; and R¹⁰, R¹², and R¹³ are N.
 34. A compoundaccording to claim 27, wherein R⁹, R¹⁴, R¹⁵, and R¹⁶ are CH; R¹⁰, R¹²,and R¹³ are N; and R¹⁷ is N or CH.
 35. A method of treating cancer,comprising administering to a patient in need thereof an effectiveamount of a compound of Formula I or a compound below: